@article {pmid41359335,
year = {2025},
author = {Cantoni, V and Casula, EP and Tarantino, B and Cupidi, C and Huber, N and Altomare, D and Premi, E and Zummo, E and Esposito, R and Leonardi, C and Herukka, SK and Solje, E and Ferrari, A and Cotelli, MS and Gasparotti, R and Martorana, A and Fracassi, C and Santarnecchi, E and Koch, G and Haapasalo, A and Grassi, M and Benussi, A and Borroni, B},
title = {Home-Based Gamma Transcranial Alternating Current Stimulation in Patients With Alzheimer Disease: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {8},
number = {12},
pages = {e2546556},
doi = {10.1001/jamanetworkopen.2025.46556},
pmid = {41359335},
issn = {2574-3805},
mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; Male ; Female ; *Transcranial Direct Current Stimulation/methods ; Aged ; Double-Blind Method ; Middle Aged ; Feasibility Studies ; Treatment Outcome ; Italy ; Electroencephalography ; Aged, 80 and over ; },
abstract = {IMPORTANCE: Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies.

OBJECTIVE: To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD.

This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate.

INTERVENTION: Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up.

MAIN OUTCOMES AND MEASURES: The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging.

RESULTS: Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale-cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study-Activities of Daily Living (-0.55; 95% CI, -0.89 to -0.21; P = .02), and Face-Name Association Test (-1.14; 95% CI, -1.66 to -0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale-cognitive subscale (-0.59; 95% CI, -1.02 to -0.16; P = .007), Alzheimer Disease Cooperative Study-Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05643326.},
}

Humans
*Alzheimer Disease/therapy/physiopathology
Male
Female
*Transcranial Direct Current Stimulation/methods
Aged
Double-Blind Method
Middle Aged
Feasibility Studies
Treatment Outcome
Italy
Electroencephalography
Aged, 80 and over

@article {pmid41359327,
year = {2025},
author = {Gotlieb, E and Joseph, B and Blank, L and Jetté, N},
title = {Barriers and Consequences of Prior Authorization for Neurologic Medications: A Scoping Review.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.4560},
pmid = {41359327},
issn = {2168-6157},
abstract = {IMPORTANCE: Prior authorization (PA) is widely used by insurers to control health care costs and promote high-value care, but it can create significant barriers to accessing medications. This is particularly concerning in neurology, where timely treatment is critical to avoid disease progression and optimize patient outcomes.

OBJECTIVE: To assess the consequences, barriers, and facilitators of PA policies affecting access to pharmacologic treatment in 6 common neurologic conditions-Alzheimer disease, Parkinson disease, multiple sclerosis, migraine, cerebrovascular disease, and epilepsy-with focus on impacts on patients, clinicians, and administrators.

EVIDENCE REVIEW: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines for scoping reviews were followed, and the study protocol was registered on Open Science Framework. MEDLINE and Embase were searched up to November 1, 2024, using Ovid for studies that assessed the role of PA as a primary or secondary outcome for the 6 included neurologic conditions, or for neurology broadly if strongly applicable to the study aim, after the signage of the Affordable Care Act in March 2010. Abstract screening and full-text review were done in duplicate. Key information was charted in extraction, including study characteristics, demographics, methods, results, and implications for relevant stakeholders. The results were aggregated and thematically analyzed.

FINDINGS: A total of 364 studies were identified using our search strategy on Ovid, 278 records were screened, and 20 studies were included in this review. The most frequently identified consequences for patients were delays in care (60%) and increase in disease activity (25%). The most frequently identified consequence for clinicians (35%) and administrators (15%) was time burden. The most common facilitators were the use of clinical pharmacists or technicians (20%) and health system specialty pharmacies (15%).

CONCLUSIONS AND RELEVANCE: According to the results of this scoping review, PA can contribute to significant access barriers for people with neurological conditions and is associated with burden for all stakeholders involved. Reforms to PA can work towards more equitable access to medications for patients.},
}

@article {pmid41358721,
year = {2025},
author = {Ke, S and Chen, Z and Qi, Y and Zhang, J and Chen, Q and Chen, J and Bo, H},
title = {Heyndrickxia coagulans as a next-generation probiotic: current evidence and future perspectives.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5fo03559g},
pmid = {41358721},
issn = {2042-650X},
abstract = {Heyndrickxia coagulans, a spore-forming probiotic, has garnered significant attention due to its exceptional tolerance to gastric acid and heat, alongside its multifaceted therapeutic potential. This review systematically delineates the unique biological characteristics of this bacterium, which include high survivability mediated by its spore form (retaining 73% viability after microwave treatment at 260 °C), dual lactate fermentation pathways, and plasticity in ATP synthesis that depends on pH and growth rate. Clinical evidence supports its efficacy in managing metabolic disorders (e.g., type 2 diabetes and non-alcoholic fatty liver disease), gastrointestinal conditions (e.g., constipation and irritable bowel syndrome), and neuropsychiatric disorders (e.g., depression and Alzheimer's disease). The underlying mechanisms involve the production of short-chain fatty acids (SCFAs), modulation of the TLR4/MyD88/NF-κB signaling pathway, and suppression of oxidative stress. Notably, therapeutic effects are strain-specific: H. coagulans MTCC 5856 (2 × 10[10] CFU day[-1]) significantly reduces abdominal distension (P < 0.01), while the strain Unique IS-2 alleviates anxiety-like behaviors by upregulating hippocampal BDNF. Although toxicological assessments establish a no observed adverse effect level (NOAEL) of >1000 mg kg[-1] in rodent models, its limited capacity for intestinal colonization presents a clinical challenge. Future research should prioritize large-scale clinical trials, multi-omics mechanistic investigations, and the development of synbiotic formulations to fully realize its potential as a next-generation therapeutic agent.},
}

@article {pmid41358632,
year = {2025},
author = {Zhang, S and Wang, T and Xue, G and Zheng, R and Ding, N and Yang, J and Zhang, M},
title = {Dysregulated mTOR signaling in Alzheimer's disease: Linking pathogenic mechanisms to emerging therapeutic strategies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400667},
doi = {10.1177/13872877251400667},
pmid = {41358632},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and multifaceted pathogenic mechanisms (including amyloid-β [Aβ] plaques, tau neurofibrillary tangles, synaptic dysfunction, and neuroinflammation). Importantly, no effective disease-modifying treatment is currently available for AD. Emerging evidence implicates dysregulated mammalian target of rapamycin (mTOR) signaling as a key contributor to AD pathogenesis. This review analyzes how aberrant mTOR signaling influences major aspects of AD pathology, including Aβ production and clearance, tau protein hyperphosphorylation, autophagy dysfunction, synaptic plasticity impairments, neuroinflammation, and oxidative stress. Notably, hyperactivated mTOR accelerates AD progression through multiple mechanisms. It promotes Aβ accumulation and tau pathology, suppresses autophagic clearance of toxic aggregates, and disrupts neuronal homeostasis, thereby exacerbating cognitive decline. Consequently, mTOR has gained attention as a therapeutic target. This review evaluates the therapeutic potential of various mTOR-targeted interventions, such as the mTORC1 inhibitor rapamycin and its analogues (rapalogs), second-generation ATP-competitive mTOR inhibitors, and certain natural compounds and traditional Chinese medicine approaches. These strategies have demonstrated promise in mitigating AD-related pathology by enhancing autophagy, reducing Aβ/tau burden, and preserving synaptic and cognitive function in preclinical studies. However, the clinical translation of mTOR-targeted therapies faces key challenges, including poor blood-brain barrier penetration of many mTOR inhibitors, potential systemic side effects, and limited clinical validation to date. Further research is needed to optimize brain delivery, dosing regimens, and target specificity to fully realize the therapeutic potential of mTOR modulation in AD.},
}

@article {pmid41358629,
year = {2025},
author = {Kandeel, M and Mahmoud, M},
title = {Comparative efficacy and safety of different brexpiprazole doses for agitation in Alzheimer's disease: A systematic review and network meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404500},
doi = {10.1177/13872877251404500},
pmid = {41358629},
issn = {1875-8908},
abstract = {BackgroundAgitation in Alzheimer's disease significantly impacts patient outcomes and caregiver burden. Brexpiprazole has emerged as a promising treatment option, but optimal dosing remains unclear.ObjectiveTo evaluate the comparative efficacy and safety of different brexpiprazole doses in treating agitation associated with Alzheimer's disease through a systematic review and network meta-analysis (NMA).MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, Web of Science, and Scopus through January 2025. Four randomized controlled trials (N = 1451) comparing various brexpiprazole doses (0.5-3 mg/day) with placebo were included. Primary outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression-Severity Scale (CGI-S), and the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) scores, alongside safety measures.ResultsBrexpiprazole 2 mg demonstrated significant improvement in CMAI scores versus placebo (mean difference [MD]: -5.88; 95% CI: -8.13 to -3.63) and CGI-S scores (MD: -0.48; 95% CI: -0.95 to -0.01). Multiple doses showed significant NPI-NH improvements, with 2-3 mg showing the strongest effect (MD: -4.60; 95% CI: -7.54 to -1.66). Higher doses (2-3 mg) increased treatment-emergent adverse events (risk ratio [RR]: 1.20-1.33) but showed no significant difference in serious adverse events compared to placebo.ConclusionsBrexpiprazole 2 mg provides optimal therapeutic benefit while maintaining a favorable safety profile. The findings support initiating treatment at lower doses with careful titration to 2 mg based on individual response and tolerability. Future research should focus on long-term outcomes and real-world effectiveness.},
}

@article {pmid41358624,
year = {2025},
author = {Seixas-Lima, B and Rosa-Neto, P and Phillips, NA and Borrie, M and Roncero, CT and Lahiri, D and Dori, D and Eintracht, S and Chertkow, H},
title = {Peripheral inflammation in a Canadian cohort of neurodegenerative conditions: Occurrence, determinants, and impact.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401611},
doi = {10.1177/13872877251401611},
pmid = {41358624},
issn = {1875-8908},
abstract = {Background"Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration.ObjectiveTo assess blood inflammatory markers in older adults. We hypothesized that elevated inflammation would be found in some cognitively normal older adults but would be more prevalent in individuals with cognitive impairment.MethodsInterleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses.ResultsWe found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts-36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep.ConclusionsPeripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.},
}

@article {pmid41357417,
year = {2025},
author = {Roy, A and Kumar, D and Bhattacharya, P and Borah, A},
title = {In silico decoding strategic pathways inhibition by coptisine for halting Alzheimer's pathology: a mechanistic insight.},
journal = {In silico pharmacology},
volume = {13},
number = {3},
pages = {202},
pmid = {41357417},
issn = {2193-9616},
abstract = {Alzheimer's Disease (AD) is a brain disorder with various neuropathological hallmarks and has become a major concern globally due to limited therapeutic options. Cholinergic dysfunction due to the depletion of acetylcholine (ACh) levels in the synapse caused by increased acetylcholinesterase (AChE) activity is one of the major factors that drives AD progression. AChE also accelerates amyloid beta (Aβ) formation and leads to amyloid plaque deposition in the brain. Production of Aβ from amyloid precursor protein (APP) with sequential cleavage by β-secretase (BACE1) and γ-secretase causes severe brain damage due to plaque toxicity. Neurofibrillary tangles (NFTs), a neuronal catastrophe resulting from hyperphosphorylation of tau protein due to upregulation of glycogen synthase kinase 3 beta (GSK3β) and downregulation of Wnt signaling because of Dickkopf-1 and low density lipoprotein receptor-related protein 6 (DKK1-LRP6) interaction, are a major pathogenic event in AD. Recent research has increasingly focused on targeting amyloidopathy, tauopathy, and cholinergic pathways as therapeutic strategies for mitigating AD pathology. Coptisine, a bioactive alkaloid having enormous pharmacological properties, including neuroprotective action, is considered in our in-silico investigation. Collective inhibition of key targets in AD pathogenesis, like AChE, β-secretase (BACE1), γ-secretase, GSK3β, and DKK1-LRP6 interaction, could be a positive approach in the arsenal of Alzheimer's treatment. In this article, we report that coptisine can inhibit these five major targets as evident from our molecular docking study, and propose it as a potential multi-target drug to play a key role in halting AD pathology. Further, comparative analysis based on predicted values of cheminformatics and pharmacokinetic profiling of coptisine and known inhibitors increases its possibility to ameliorate AD. However, robust research, including a preclinical and clinical study on coptisine for its safety and efficacy assessment against AD pathology, is warranted for its validation as an anti-AD drug.},
}

@article {pmid41357230,
year = {2025},
author = {Xu Lou, I and Zhou, H and Wan, H},
title = {The critical role of Th17 cells and IL-17A in autoimmune and inflammation-associated neurological diseases: mechanisms and therapeutic perspectives.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1656422},
pmid = {41357230},
issn = {1664-3224},
mesh = {Humans ; *Th17 Cells/immunology/metabolism ; *Interleukin-17/immunology/metabolism ; Animals ; Inflammation/immunology ; *Autoimmune Diseases/immunology/therapy ; *Nervous System Diseases/immunology/therapy/etiology/metabolism ; *Neuroinflammatory Diseases/immunology/therapy ; },
abstract = {Helper T cells 17 (Th17) and their effector cytokine, interleukin-17A (IL-17A), play a dual role in immune homeostasis. On one hand, they are essential in defense against extracellular pathogens, such as bacteria and fungi, by inducing chemokine production and recruiting neutrophils. On the other hand, their dysregulated activity is strongly linked to autoimmune and inflammatory disorders, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and others. This article reviews the molecular mechanisms regulating Th17 differentiation and function, emphasizing the role of transcription factors like RORγt and RORα, as well as the influence of cytokines such as IL-6, IL-23, and TGF-β. Additionally, it explores the imbalance between pro-inflammatory Th17 cells and regulatory T cells (Tregs), a critical axis in the pathogenesis of autoimmune and neuroinflammatory diseases. In the context of neurological disorders, Th17 cells can infiltrate the central nervous system (CNS), where they contribute to neuroinflammation by activating microglia and astrocytes, exacerbating damage in conditions such as multiple sclerosis, traumatic brain injury, and neurodegenerative diseases. Emerging therapies, including anti-IL-17 monoclonal antibodies and natural modulators, are discussed as potential strategies to restore the Th17/Treg balance without compromising protective immunity. Finally, the need for further research is highlighted to elucidate the specific mechanisms of Th17 infiltration into the CNS, their interaction with the gut microbiota, and the development of personalized therapies. The integration of immunological, metabolic, and environmental approaches offers promising perspectives for the treatment of Th17/IL-17-mediated diseases.},
}

Humans
*Th17 Cells/immunology/metabolism
*Interleukin-17/immunology/metabolism
Animals
Inflammation/immunology
*Autoimmune Diseases/immunology/therapy
*Nervous System Diseases/immunology/therapy/etiology/metabolism
*Neuroinflammatory Diseases/immunology/therapy

@article {pmid41357129,
year = {2025},
author = {Rananaware, P and Singh, S and Brahmkhatri, VP},
title = {Scavenging of reactive oxygen and nitrogen species using nanoparticles and their applications in disease management.},
journal = {RSC advances},
volume = {15},
number = {56},
pages = {47955-47980},
pmid = {41357129},
issn = {2046-2069},
abstract = {Nanomaterials constitute a new trend of disease management that is associated with advanced nanotechnology and bioengineered materials, presenting new solutions for various diseases that were previously problematic to handle with traditional chemical drugs or natural materials. Due to their high surface area, charge, variable size, and other properties, nanomaterials have been broadly used to manage several diseases. Specifically, nanomaterials have appeared with a significant ability to act as RONS scavengers for treatment and disease management. This is a result of their versatility in various applications, controlled release, enhanced reactivity, and unique biochemical properties. Recently, specific nanomaterials for treatment and disease management have been effectively developed into clinical tests. This review article focuses on the different types of nanomaterials that are effective for RONS scavenging and are used for different biomedical applications associated with excessive RONS generation. Nanoparticle-based systems have gained significant attention in recent years for their potential applications in scavenging reactive oxygen and nitrogen species (RONS) as part of disease management strategies. These nanoparticles can be designed to enhance the delivery, stability, and efficacy of antioxidants or other scavenging agents. The current review article provides a complete overview of the anti-inflammatory nature and use of nanoparticle systems by examining the molecular and pathological mechanisms of oxidative stress and the function of this stress in both cell and tissue damage. However, it is important to consider the biocompatibility, stability, and potential toxicity of these nanoparticle systems for therapeutic applications. Additionally, targeted delivery and controlled release mechanisms can enhance their efficacy in scavenging RONS at specific disease sites. RONS play a dual role in biological systems-they are essential for various physiological processes, such as cell signalling and host defence, but their overproduction can lead to oxidative and nitrosative stress, contributing to the development and progression of several diseases. Managing RONS is a key aspect of disease prevention and treatment. This article focuses on the use of nanomaterials for the treatment of various cancers, and in other areas such as tissue engineering, wound healing, osteoclast genesis, inflammation, and neurodegenerative disorders, such as Parkinson's and Alzheimer's disease, through RONS scavenging.},
}

@article {pmid41356945,
year = {2025},
author = {Kumar, P and Bhat, A and Goel, D and Mittal, M},
title = {Clinico-Etiological Profile of Young-Onset Dementia From a Tertiary Care Center in Northern India.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96203},
pmid = {41356945},
issn = {2168-8184},
abstract = {BACKGROUND: This study examines young-onset dementia (YOD). Young-onset dementia refers to cases of dementia that manifest earlier in life and often pose unique clinical and management challenges. Despite its significant impact, data on YOD in northern India remain limited.

OBJECTIVE: To evaluate the clinico-etiological profile and cognitive characteristics of young-onset dementia patients presenting to a tertiary care center in Uttarakhand, India.

METHODS: This is a longitudinal follow-up study that was conducted over 1.5 years in the Department of Neurology. A total of 37 patients under 65 years of age out of 40 selected, diagnosed with major neurocognitive disorder (DSM-5), were included. Comprehensive clinical assessments, brain imaging, and cognitive evaluations were conducted. Data were analyzed using IBM Corp. Released 2018. IBM SPSS Statistics for Windows, Version 24. Armonk, NY: IBM Corp., with chi-square tests, analysis of variance (ANOVA), and Bonferroni corrections, with significance set at p<0.05.

RESULTS: The majority of patients were males (65%) and aged 56 to 65 years (50%). Vascular dementia was the most common cause (37.8%), followed by Alzheimer's disease (18.9%) and frontotemporal dementia (13.5%). Based on the verbal-language/orientation-memory (VLOM) ratio, 27.5% had frontotemporal-type dementia and 7.5% had Alzheimer-type dementia. Significant cognitive decline (p < 0.05) in MMSE and ACE-III scores was observed in Alzheimer's disease and frontotemporal dementia. Vitamin B12 deficiency showed 13.5% improvement with treatment. VLOM ratios effectively differentiated frontotemporal dementia (FTD) from AD.

CONCLUSION: This study concluded that vascular dementia is the leading cause of YOD in this region, reflecting a high burden of modifiable vascular risk factors. The VLOM ratio offers diagnostic value in distinguishing dementia subtypes. Early identification and intervention are essential to address the functional burden of YOD.},
}

@article {pmid41356558,
year = {2025},
author = {Wang, H and Yang, F and Gao, Z and Cheng, Z and Liang, X},
title = {The gut-brain axis in Alzheimer's disease: how gut microbiota modulate microglial function.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1704047},
pmid = {41356558},
issn = {2673-6217},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that can be caused by multiple factors, such as abnormal amyloid-beta (Aβ) deposition, pathological changes in Tau protein, lipid metabolism disorders, and oxidative stress. Recent studies have revealed the potential link between gut microbiota and AD, particularly the impact of gut microbiota and its derivatives on microglia. As immune cells in the central nervous system (CNS), microglia are involved in neuroinflammation and the regulation of cognitive function. Research indicates that the dysregulation of gut microbiota may affect the phenotype and function of microglia through various mechanisms, including direct metabolite action and indirect immune and neurotransmitter regulation. This article reviews the direct and indirect effects of gut microbiota and its derivatives on microglia, explores their role in the pathogenesis of AD, and discusses therapeutic strategies based on gut microbiota, such as dietary regulation, probiotics, fecal microbiota transplantation, and traditional Chinese medicine. Although existing studies have shown the potential of these interventions, further research is needed to completely understand their application in the treatment of AD.},
}

@article {pmid41355970,
year = {2026},
author = {Park, A and Hong, SM and Lee, Y and Lee, J and Jeon, S and Seo, SY and Lee, J and Kim, SH and Ko, EJ and Lee, HR and Jung, SH and Bae, M and Kang, MC and Park, MG and Nam, S and Kim, SY},
title = {Deep learning identifies TP-41 for methylglyoxal scavenging in Alzheimer's treatment.},
journal = {Theranostics},
volume = {16},
number = {3},
pages = {1103-1122},
pmid = {41355970},
issn = {1838-7640},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Pyruvaldehyde/metabolism ; Animals ; *Deep Learning ; Mice ; Disease Models, Animal ; Glycation End Products, Advanced/metabolism ; Humans ; Male ; Memory Disorders/drug therapy ; Mice, Inbred C57BL ; },
abstract = {Rationale: Increased levels of advanced glycation end products (AGEs) have been observed in the brain tissues of patients with Alzheimer's disease (AD). Methylglyoxal (MGO) is a potent precursor of AGEs. To date, there have been no reports of utilizing deep learning (DL) technologies to target MGO scavengers for the development of AD therapeutics. Therefore, DL-driven approaches may play a crucial role in identifying potential MGO scavengers and candidates for Alzheimer's treatment. Methods: We developed "DeepMGO," a novel DL-based MGO scavenging activity prediction model, trained on 2,262 MGO scavenging activity assays from 660 compounds. Using this approach, we identified and validated TP-41 as a potential MGO scavenger in a mouse model of memory impairment. Results: DeepMGO demonstrated robust predictive performance and identified novel compounds with high MGO scavenging activity. TP-41 ameliorated depression symptoms and memory deficits in mouse models. Conclusions: Using DeepMGO, we identified TP-41 as a potential therapeutic agent for AD.},
}

*Alzheimer Disease/drug therapy/metabolism
*Pyruvaldehyde/metabolism
Animals
*Deep Learning
Mice
Disease Models, Animal
Glycation End Products, Advanced/metabolism
Humans
Male
Memory Disorders/drug therapy
Mice, Inbred C57BL

@article {pmid41355958,
year = {2026},
author = {Wu, Y and Fan, Y and Bao, S and Song, Y and Wang, R and Wu, J and Liu, X and Jin, J and Kong, L and Hou, B and Liang, P and Chen, T and Liu, W and Peng, B and He, F and Zhou, Y and Xu, J and Chen, Y and Han, S and Yin, J and He, X},
title = {Mertk promotes early microglial-mediated synaptic engulfment in Alzheimer's disease.},
journal = {Theranostics},
volume = {16},
number = {3},
pages = {1238-1261},
pmid = {41355958},
issn = {1838-7640},
mesh = {*Microglia/metabolism ; *Alzheimer Disease/metabolism/pathology/genetics ; *c-Mer Tyrosine Kinase/metabolism/genetics ; Animals ; Mice ; *Synapses/metabolism/pathology ; Disease Models, Animal ; Phagocytosis ; Hippocampus/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; PPAR gamma/metabolism ; Mice, Knockout ; Mice, Inbred C57BL ; Humans ; Mice, Transgenic ; Male ; },
abstract = {Rationale: Synaptic deficits occur prior to the emergence of Aβ plaques and tau pathology in Alzheimer's disease (AD). Dysregulated microglia excessively prune synapses, leading to synaptic loss. While microglia phagocytic receptor Mertk participates in synaptic pruning, the role of Mertk in driving early synaptic loss in AD remains elusive. Methods: Single-cell RNA sequencing (scRNA-seq) was used to analyze transcriptional changes of microglia in early stage of AD mice. Mertk-mediated synaptic engulfment was investigated both in vivo and in vitro. Results: Phagocytic-associated microglia with upregulated Mertk were identified in the early stage of AD mice. Dysregulated synaptic pruning by microglia caused hippocampal synaptic loss and memory deficits in two AD mouse models. Notably, Mertk knockout or antagonist treatment reversed excessive synapse elimination by microglia. Mechanistically, Aβo-induced PPARγ promoted Mertk transcription, mediating microglial phagocytosis of synapses. Conclusions: Collectively, our findings suggest that PPARγ-regulated, Mertk-mediated microglial synaptic engulfment contributes to early synaptic loss in AD, highlighting microglial Mertk as a potential therapeutic target for AD.},
}

*Microglia/metabolism
*Alzheimer Disease/metabolism/pathology/genetics
*c-Mer Tyrosine Kinase/metabolism/genetics
Animals
Mice
*Synapses/metabolism/pathology
Disease Models, Animal
Phagocytosis
Hippocampus/metabolism/pathology
Amyloid beta-Peptides/metabolism
PPAR gamma/metabolism
Mice, Knockout
Mice, Inbred C57BL
Humans
Mice, Transgenic
Male

@article {pmid41355756,
year = {2025},
author = {Liu, F and Tang, YL and Zhang, ZB and Tan, YH and Lin, SH and Wang, NY and Li, JN and Pan, ZJ and Li, JF and Huang, JF and Ding, YQ and Guo, CM and Xu, L and Peng, C and Zhou, QX},
title = {Modifying Glucose Metabolism Reverses Memory Defects of Alzheimer's Disease Model at Late Stages.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e06695},
doi = {10.1002/advs.202506695},
pmid = {41355756},
issn = {2198-3844},
support = {2022ZD0204900//National Program of Brain Science and Brain-Inspired Intelligence Technology 2030/ ; 32271080//National Natural Science Foundation of China/ ; 32071029//National Natural Science Foundation of China/ ; 82473909//National Natural Science Foundation of China/ ; 32170662//National Natural Science Foundation of China/ ; 32070818//National Natural Science Foundation of China/ ; 202401AS070131//Yunnan Fundamental Research Project/ ; 202402AA310014//Yunnan Provincial Science and Technology Department/ ; LG-QS-202205-05//The Lingang Laboratory/ ; 202001BB050005//Natural Science Foundation of Yunnan Province/ ; //Xingdian talent program of Yunnan Province/ ; },
abstract = {Significant efforts have harvested a sophisticated understanding of Alzheimer's disease (AD) including amyloid beta (Aβ) cascade mechanisms, although effective treatment for reversing or stopping AD progression is not available. This study reports that ferul enanthate (SL), a novel derivative of active agents targeting brain microvessels, oxidative phosphorylation, and ATP generation can reverse the hippocampus-dependent spatial memory defects and reduce Aβ plaques in AD model mice (APP/PS1) at advanced stages. Spatial transcriptomics discovers that SL endows a cluster of genes expressing in Aging-AD-Rescue (AAR) pattern, which is prominent in hippocampal dendritic region where Aβ plaques are densely deposited. Furthermore, this AAR rule covers hippocampal Glut1 (glucose transporter 1) expression and ATP generation, which are further confirmed by immunoblotting or immunofluorescence studies. Our data demonstrate that SL can still reverse memory defects at advanced stages of AD mice by modifying aging-dependent multiple pathologies of AD, particularly promoting Glut1 expression and ATP generation.},
}

@article {pmid41355547,
year = {2025},
author = {Lu, Q and Di, X and Guo, X},
title = {Comprehensive Review on the Protective Effects of Lycium barbarum Polysaccharide on Neurodegenerative Diseases.},
journal = {Endocrine, metabolic & immune disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715303393082251027072838},
pmid = {41355547},
issn = {2212-3873},
abstract = {Neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, ischemic stroke, and other related conditions, significantly impact the quality of life, particularly in low-income nations. The pathogenesis of these diseases is driven by neuroinflammation, oxidative stress, apoptosis, mitochondrial dysfunction, and regulation of autophagy. To date, no therapies or medications can fully reverse the progression of these diseases. Natural polysaccharides have demonstrated significant therapeutic potential in the treatment of neurodegenerative diseases. Lycium barbarum polysaccharide, derived from the traditional Chinese medicine Lycium barbarum L., has attracted considerable attentionfor its diverse biological activities, biodegradability, ease of modification, and low toxicity. This review aims to systematically evaluate the neuroprotective effects of Lycium barbarumpolysaccharides and their mechanisms in various neurodegenerative disease models. For this study, we used multiple scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. We verified the correct plant name through the website plantlist.org. The search results were interpreted and documented based on the retrieved bibliographic information. Lycium barbarum polysaccharide has shown significant therapeutic potential for the treatment of neurodegenerative diseases. Experimental evidence reveals its neuroprotective effects through various mechanisms, including reducing neuroinflammation, alleviating oxidative stress, inhibiting apoptosis, improving mitochondrial function, and regulating autophagy. The current review established that Lycium barbarum polysaccharide holds promise as a therapeutic agent for neurodegenerative diseases. However, further research is required to address the limitations identified in previous studies and to guide future experimental investigations and clinical applications.},
}

@article {pmid41355080,
year = {2025},
author = {van Dyck, CH and Sperling, R and Johnson, K and Dhadda, S and Kanekiyo, M and Li, D and Gee, M and Hersch, S and Irizarry, M and Kramer, L},
title = {Long-term safety and efficacy of lecanemab in early Alzheimer's disease: Results from the clarity AD open-label extension study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70905},
doi = {10.1002/alz.70905},
pmid = {41355080},
issn = {1552-5279},
support = {//Eisai Inc. and Biogen/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; Female ; Male ; Aged ; Quality of Life ; Treatment Outcome ; Disease Progression ; Amyloid beta-Peptides ; Aged, 80 and over ; },
abstract = {INTRODUCTION: In Clarity AD, lecanemab reduced markers of amyloid in early symptomatic Alzheimer's disease and slowed cognitive and functional decline at 18 months. Herein, we report 36-month data from the ongoing open-label extension (OLE).

METHODS: Clarity AD is an 18-month, randomized study (Core), with an OLE where participants received open-label lecanemab. Clinical and health-related quality-of-life (HRQoL) outcomes were evaluated overall and by examining "delayed-start" and "early-start" cohorts. Low pathology (i.e., low baseline amyloid or tau) subgroups were analyzed.

RESULTS: ARIA rates were low after 6 months and not associated with long-term progression. Across clinical and HRQoL endpoints, lecanemab-treated participants continued to benefit through 36 months. Separation between early and delayed start was maintained between 18 and 36 months. The low pathology subgroup showed stability or improvement over 18-36 months.

DISCUSSION: Benefit continued to accrue with ongoing lecanemab treatment through 36 months. Results in the low pathology subgroup support early initiation of lecanemab treatment.

HIGHLIGHTS: This research evaluated the long-term efficacy, safety, and HRQoL results from an ongoing extension of the phase 3 Clarity AD, which included open-label lecanemab treatment for up to 36 months. Overall, the results show participants continue to accrue a lecanemab treatment benefit up to 36 months and highlight the importance of continued long-term lecanemab treatment. Results presented in our paper demonstrate that lecanemab continued suppression of amyloid plaque levels and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 36 months to date. No new safety signals were observed with continued lecanemab treatment. After the first 6 months, ARIA rates were low and similar to ARIA rates on placebo, with no association between ARIA occurrence and accelerated long-term clinical progression. Taken together with existing data, these results provide a clear rationale and a demonstration of the disease modification effects of long-term lecanemab therapy.},
}

Humans
*Alzheimer Disease/drug therapy/pathology
Female
Male
Aged
Quality of Life
Treatment Outcome
Disease Progression
Amyloid beta-Peptides
Aged, 80 and over

@article {pmid41354641,
year = {2025},
author = {Feyzbakhsh, H},
title = {Nanoparticle-based strategies for overcoming the blood-brain barrier in CNS disorders and brain cancer: precision diagnostics and therapeutics for Alzheimer's, Parkinson's, multiple sclerosis, and glioblastoma.},
journal = {Tissue barriers},
volume = {},
number = {},
pages = {2599564},
doi = {10.1080/21688370.2025.2599564},
pmid = {41354641},
issn = {2168-8370},
abstract = {Nanoparticle (NP)-based technologies are transforming the management of central nervous system (CNS) disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and brain cancer (BC), glioblastoma, by surpassing the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). This review integrates NP approaches, comprising organic (e.g. liposomes, polymeric NPs), inorganic (e.g. gold, iron oxide), carbon-based, and hybrid systems, to overcome disease-specific barriers. In AD, superparamagnetic iron oxide NPs (SPIONs) and gold NPs (AuNPs) improve amyloid-beta plaque and tau protein detection, while liposomes precisely deliver anti-amyloid drugs. For PD, dopamine-loaded liposomes and cerium oxide NPs reinstate dopaminergic function and decrease oxidative stress, with improved motor outcomes. In MS, PEGylated liposomes and PLGA NPs regulate autoimmune responses, inducing remyelination and attenuating neuroinflammation. For BC, dendrimers and magnetic NPs facilitate targeted chemotherapy delivery across the BBB/BBTB, improving glioblastoma treatment outcomes. We compare NP types critically based on physicochemical characteristics, efficacy, toxicity, and clinical translation potential, highlighting gaps in long-term safety and scalability. Challenges like NP toxicity and regulatory complexities are discussed, suggesting biocompatible designs and standardized FDA/EMA pathways. By consolidating diagnostic and therapeutic innovations, this review outlines a roadmap for NP-based precision medicine, paving the way for clinical translation and better patient outcomes in CNS disorders and brain cancer.},
}

@article {pmid41354326,
year = {2025},
author = {Wiredu, K and Gowda, P and Rhee, J and Mueller, A and Simon, C and Graves, OK and Qu, JZ and Spite, M and McKay, TB and Akeju, O},
title = {Long-chain polyunsaturated fatty acid lipid and oxylipin alterations in postoperative delirium after cardiac surgery.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {100959},
doi = {10.1016/j.jlr.2025.100959},
pmid = {41354326},
issn = {1539-7262},
abstract = {Lipids play a crucial role in signaling, membrane dynamics, and inflammatory regulation, yet their involvement in postoperative delirium pathogenesis remains unclear. This study examined serum lipidomic alterations in postoperative delirium and assessed the effects of dexmedetomidine treatment on these changes. Lipidomic profiling was conducted at baseline and postoperative day one in two independent cohorts of cardiac surgery patients. Mass spectrometry-based shotgun lipidomics and targeted lipid analyses were used to assess lipidomes and oxylipins, respectively. Cardiac surgery was associated with decreased serum lysophospholipids. Postoperative delirium was associated with increased long-chain polyunsaturated fatty acid phospholipids (LCPUFA-PLs), particularly phosphatidylethanolamines (PEs), and elevated oxylipins. Dexmedetomidine, a potential delirium-mitigating medication, reduced LCPUFA-PLs. These findings highlight lipid modulation as a potential target for postoperative delirium prevention.},
}

@article {pmid41353845,
year = {2025},
author = {Azadmaleki, H and Zolnour, A and Rashidi, S and Noble, JM and Hirschberg, J and Esmaeili, E and Morovati, T and Zolnoori, M},
title = {TransformerCARE: A novel speech analysis pipeline using transformer-based models and audio augmentation techniques for cognitive impairment detection.},
journal = {International journal of medical informatics},
volume = {207},
number = {},
pages = {106208},
doi = {10.1016/j.ijmedinf.2025.106208},
pmid = {41353845},
issn = {1872-8243},
abstract = {OBJECTIVE: Early diagnosis of cognitive impairment, including Alzheimer's and other dementias, is critical for effective treatment and slowing disease progression. However, over 50% of cases remain undiagnosed until advanced stages due to limitations in current methods. Recognizing speech impairments as early markers of cognitive decline, this study evaluated the utility of speech analysis as a technique for early detection. We introduce TransformerCARE, a speech processing pipeline utilizing advanced speech transformer models.

METHODS: TransformerCARE incorporated a series of key steps, including preprocessing, speech segmentation, transformer fine-tuning, segment aggregation, performance evaluation, and data augmentation. In the fine-tuning step, we evaluated the performance of four state-of-the-art speech transformer models: Wav2vec 2.0, HuBERT, WavLM, and DistilHuBERT. For data augmentation, we adopted multiple techniques, with particular emphasis on frequency masking due to its ability to preserve subtle acoustic cues associated with cognitive impairment. We measured the performance of TransformerCARE on the ADReSSo Challenge dataset from DementiaBank, comprising 237 subjects (122 cognitively impaired and 115 cognitively normal).

RESULTS: TransformerCARE demonstrated its highest performance with HuBERT, achieving an AUC of 81.80 (F1-score = 79.31) using an aggregation technique that averaged embeddings of 14-second speech segments. Augmenting the training data with frequency masking improved performance by 5 %, resulting in an AUC of 86.11 (F1-score = 84.63). We also demonstrated that incorporating clinicians' speech during patient interactions can improve the performance of the pipeline. Our error analysis revealed significant differences between the acoustic patterns of correctly identified negative cases (true negatives) and those incorrectly identified as positive (false positives), as well as between correctly identified positive cases (true positives) and those incorrectly identified as negative (false negatives). This indicates specific deviations in speech characteristics among inaccurately diagnosed subjects.

CONCLUSION: In summary, TransformerCARE demonstrates strong potential for integration into clinical workflows as a screening tool for cognitive impairment, aiding in the timely and appropriate care of affected patients.},
}

@article {pmid41353509,
year = {2025},
author = {Kolouei, A and Barati, M and Abbas-Mohammadi, M},
title = {Investigating the binding potential of the Melissa officinalis oil against Alzheimer's targets by molecular docking and in vitro evaluations.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30232-w},
pmid = {41353509},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with limited treatment options. Melissa officinalis (M. officinalis), traditionally used for its medicinal properties, contains compounds that may offer therapeutic benefits for AD. We extracted essential oils from M. officinalis using supercritical CO2 and identified 31 compounds via GC-MS, supplemented by 20 non-volatile compounds from the Dictionary of Natural Products. Molecular docking was performed against five AD-related targets: β-Secretase, γ-Secretase, amyloid-β) A(, neprilysin, and acetylcholinesterase. The oil's antioxidant capacity and cytotoxicity on PC12 cells were evaluated using DPPH and MTT assays, respectively. Docking analysis revealed that sajerinic acid had the highest affinity for acetylcholinesterase, neprilysin, and γ-Secretase. Aβ and β-Secretase were most affected by 3',4',5,7-tetrahydroxyflavone, 3'-O-β-D-glucuronopyranoside, γ-O-β-D-glucopyranoside and 2,3,19,23-tetrahydroxy-12-ursen-28-oic acid-23-sulfate, 28-O-β-D-glucopyranosyl ester, respectively. Among oil compounds, triethyl citrate showed the highest affinity for β-Secretase, neprilysin, and γ-Secretase, while 2,2-dimethoxybutane exhibited the highest potential for interaction with Aβ and acetylcholinesterase. The oil reduced PC12 cell survival in a dose-dependent manner. The extract also displayed significant antioxidant activity, suggesting a potential to reduce oxidative stress. These findings suggest that M. officinalis contains compounds with potential anti-Alzheimer's properties, warranting further investigation. The identified compounds could serve as leads for developing novel therapeutics, and the antioxidant activity of the extract supports its traditional use in managing neurodegenerative conditions. Further studies are needed to validate these findings in vivo and explore the therapeutic potential of M. officinalis in AD.},
}

@article {pmid41352683,
year = {2025},
author = {Shim, GH and Lau, ECY and Huynh, ALH and Lu, CY and Tan, ECK},
title = {Influence of patient characteristics on efficacy and safety of anti-amyloid monoclonal antibodies in Alzheimer's disease: A systematic review and meta-analysis.},
journal = {Ageing research reviews},
volume = {114},
number = {},
pages = {102981},
doi = {10.1016/j.arr.2025.102981},
pmid = {41352683},
issn = {1872-9649},
abstract = {BACKGROUND: Lecanemab and donanemab are the first anti-amyloid monoclonal antibodies (mAbs) clinically available as disease-modifying therapies for Alzheimer's disease (AD). However, it remains unclear whether their treatment effects differ across demographic, clinical, or genetic subgroups.

OBJECTIVE: This systematic review aimed to explore how patient characteristics modify the efficacy, safety and humanistic outcomes of anti-amyloid mAbs lecanemab and donanemab in patients with early AD.

METHODS: A systematic search of MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library was conducted from database inception to July 30th, 2025, using a combination of keywords and Medical Subject Heading terms relating to lecanemab and donanemab. Meta-analyses were conducted for safety outcomes where sufficient data was available.

RESULTS: Sixteen studies representing six randomised clinical trials (total N = 5633) were included. Both lecanemab and donanemab showed the greatest slowing of cognitive decline in White/Caucasian patients and apolipoprotein E4 (ApoE4) non-carriers. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) and microhemorrhages (ARIA-H) were more prevalent in ApoE4 carriers. The risk of ARIA-E was 2.19 times higher (95 %CI:1.91-2.50) and ARIA-H was 3.45 times higher (95 %CI:1.35-8.72) in ApoE4 carriers versus non-carriers. Statistically significant improvements in health-related quality of life were observed with lecanemab in ApoE4 heterozygous participants and in those aged 65-74 years.

CONCLUSIONS: The efficacy and safety of anti-amyloid mAbs in AD may differ based on patients' demographic and genetic factors. These findings highlight the potential for personalised treatment strategies and inform national drug policies. Further research is needed to evaluate long-term outcomes and address under-studied patient populations.

SUMMARY: The efficacy and safety of lecanemab and donanemab varied across patient subgroups, including age, sex, race/ethnicity and genetic factors such as ApoE4 genotype status. The risk of ARIA was higher in ApoE4 carriers, particularly the homozygous.},
}

@article {pmid41352634,
year = {2025},
author = {Geleta, LA and Doyle, C and Garton, FC and Fowler, M and Carr, JM and Akkari, PA and McRae, AF and Rogers, ML and Madakkatel, I and Benyamin, B},
title = {The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review.},
journal = {Brain, behavior, and immunity},
volume = {132},
number = {},
pages = {106201},
doi = {10.1016/j.bbi.2025.106201},
pmid = {41352634},
issn = {1090-2139},
abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.

METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, PsycINFO, Scopus, Web of Science, CINAHL, and Emcare to identify relevant studies. Two independent reviewers screened studies, assessed quality, and extracted data. Qualitative synthesis was conducted for all included NDDs, specifically Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), and due to data availability, meta-analysis was used to assess the impact of HERVs antibodies on ALS only.

RESULTS: Twenty-six studies (N ranges: 6-485) met the inclusion criteria, with majority focusing on HERV-K and ALS. Across studies, the association between HERV expression and NDDs was inconsistent, particularly for ALS, PD, and FTD, whereas investigations in AD showed a more consistent upregulation of specific HERVs. Studies relying on polymerase chain reaction (PCR) (typically smaller) showed inconsistent associations (21 studies), while RNA sequencing studies reported consistent associations (9 studies). A preliminary meta-analysis revealed a fivefold increase [OR: 5.83; 95 % CI: 4.14, 8.18] in ALS risk among participants with positive HERV antibodies.

CONCLUSIONS: The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs' role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.},
}

@article {pmid41351718,
year = {2025},
author = {Krishnan, M and Kumaresan, M and Ravi, S and Martin, LC and Manikandan, B and Raman, T and Ramar, M},
title = {Bornyl Acetate and Menthol Provide Neuroprotection Against Lipopolysaccharide-Induced Alzheimer's Disease-Like Condition in C57BL/6 Mice by Downregulating NARC-1 Lipid Antagonist.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {262},
pmid = {41351718},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology/prevention & control ; Mice, Inbred C57BL ; Lipopolysaccharides ; *Menthol/pharmacology/therapeutic use ; *Down-Regulation/drug effects ; Male ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurological illness that causes Aβ deposition and cognitive impairments. Anti-cholinesterase and anti-depressant drugs are used as medications; however, their side effects spotlight the need for alternate treatments. Bornyl acetate and menthol are monoterpenes with bioactive potential investigated against inflammation induced by lipopolysaccharide (LPS) in C57BL/6 mice. In our study, we analysed various behavioural changes along with memory activities as well as assessed neuronal damage, acetylcholinesterase activity, amyloid deposition, mitochondrial membrane integrity, calcium deposition and oxidation derivatives. In addition, we also examined gene and protein expression associated with lipid dysfunction in neuroinflammation. Our findings revealed that monoterpenes such as bornyl acetate and menthol potentially improved LPS-induced behaviour changes and cognitive activities. In addition, these compounds have the potential effects against amyloid plaque formation, calcium build-up, mitochondrial membrane damage and oxidative markers (malondialdehyde, protein carbonyls and advanced glycation end products) in the LPS-injected C57BL/6 mice. Treatment with bornyl acetate and menthol also inhibited neural apoptosis-regulated convertase (NARC-1)/proprotein convertase subtilisin/kexin type 9 (PCSK-9) by upregulating low-density lipoprotein receptor-related protein (LRP)-1 protein expression. Cholesterol oxidation genes, including 11β-hydroxysteroid dehydrogenase 1 & 2, as well as proinflammatory microglial, apoptotic and amyloidogenic protein and gene expression, were decreased respectively when treated with monoterpenes while promoting the upregulation of anti-inflammatory. Based on the results, we concluded that these compounds can potentially target and prevent neuroinflammation, including Alzheimer's disease.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology/prevention & control
Mice, Inbred C57BL
Lipopolysaccharides
*Menthol/pharmacology/therapeutic use
*Down-Regulation/drug effects
Male
*Neuroprotective Agents/pharmacology/therapeutic use
Mice
*Neuroprotection/drug effects
Oxidative Stress/drug effects

@article {pmid41351658,
year = {2025},
author = {Singh, I and Singh, AK},
title = {Senolytics as Modulators of Critical Signaling Pathways: a Promising Strategy to Combat Brain Aging and Neurodegenerative Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {261},
pmid = {41351658},
issn = {1559-1182},
support = {CRG/2022/006612//Anusandhan National Research Foundation/ ; },
mesh = {Humans ; *Aging/drug effects/metabolism/pathology ; *Signal Transduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Brain/drug effects/metabolism/pathology ; Animals ; *Senotherapeutics/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Aging of the brain, an intricate process, is a significant risk factor for neurodegenerative disorders (NDDs), such as Alzheimer's disease and Parkinson's disease. Senescent cell accumulation is an important hallmark of brain aging. These cells resist apoptotic cell death, produce proinflammatory cytokines, increase oxidative stress, and store toxic proteins that exacerbate neurodegeneration. These senescent cells cause neuroinflammation and dysfunction of the neuronal microenvironment by transmitting senescent phenotypes to neighboring healthy cells. Senolytics have become a viable treatment option to reduce the effects of brain aging since they specifically target and destroy senescent cells. Numerous senolytic compounds, such as dasatinib, fisetin, and quercetin, effectively eliminate senescent cells and reduce the accumulation of harmful substances, including misfolded toxic protein aggregates and reactive oxygen species, thereby helping to maintain tissue homeostasis. These medications aid in reducing oxidative stress and inflammation, two significant factors in brain aging and NDDs, by encouraging the removal of senescent cells. The key molecules involved in this process are mTOR, Nrf2-Keap1, AMPK, and Sirtuin 1 (SIRT1). The modulation of the mTOR and AMPK pathways affects autophagy and cellular metabolism, facilitating the elimination of harmful accumulations and damaged cell organelles. In addition, cellular repair and improved antioxidant defense are encouraged by the activation of the SIRT1 and Nrf2 pathways. The combination of senolytic therapy with these signaling pathways provides a novel approach to attack the cellular and molecular foundations of brain aging and neurodegenerative disorders.},
}

Humans
*Aging/drug effects/metabolism/pathology
*Signal Transduction/drug effects
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Brain/drug effects/metabolism/pathology
Animals
*Senotherapeutics/pharmacology/therapeutic use
Oxidative Stress/drug effects

@article {pmid41350983,
year = {2025},
author = {Deng, H and Lee, TA and Gaber, CE and Kim, K and Crawford, SY and Bayliss, EA and Singh, S and Young, JG and Toh, S and Li, X},
title = {Treatment patterns of symptomatic treatments for Alzheimer's disease and related dementias.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-025-06745-4},
pmid = {41350983},
issn = {1471-2318},
}

@article {pmid41350761,
year = {2025},
author = {He, H and Razlighi, QR and Gazes, Y and Habeck, C and Stern, Y and , },
title = {Integrating individualized connectome with amyloid pathology improves predictive modeling of future cognitive decline.},
journal = {Communications medicine},
volume = {5},
number = {1},
pages = {515},
pmid = {41350761},
issn = {2730-664X},
support = {R01 AG038465/AG/NIA NIH HHS/United States ; R01 AG026158/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: The deposition of amyloid-β (Aβ) in the human brain is a hallmark of Alzheimer's disease and is associated with cognitive decline. Aβ pathology is traditionally assessed at the whole-brain level across neocortical regions using positron emission tomography (PET). However, these measures often show weak associations with future cognitive impairment. A more sensitive pathology metric is needed to quantify early Aβ burden and better predict cognitive decline. Here, we aim to develop a network-based metric of Aβ burden to improve early prediction of cognitive decline in aging populations.

METHODS: We integrated subject-specific brain connectome information with Aβ-PET measures to construct a network-based metric of Aβ burden. Cross-validated predictive modeling was used to evaluate the performance of this metric in predicting longitudinal cognitive decline. Furthermore, we identified a neuropathological signature pattern linked to future cognitive decline, and we validated this pattern in an independent cohort.

RESULTS: Our results demonstrate that incorporating individualized structural connectome, but not functional connectome, information into Aβ measures enhances predictive performance for prospective cognitive decline. The identified neuropathological signature pattern is reproducible across cohorts.

CONCLUSION: These findings advance our understanding of the spatial patterns of Aβ pathology and its relationship to brain networks, highlighting the potential of connectome-informed network-based metrics for Aβ-PET imaging in identifying individuals at higher risk of cognitive decline.},
}

@article {pmid41350438,
year = {2025},
author = {Liu, D and Li, X and Shi, P and Hong, W and Huang, J and Hou, M and Ma, L and Liao, Q and Yang, H and Fu, X and Zhou, H and Lu, J and Liu, Y and Feng, X and Wang, D and Zhou, R},
title = {7,8-Dihydroxyflavone ameliorates bone loss by regulating TRKB/AKT/FOXO3a pathway in a mouse model of alzheimer's disease.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41350438},
issn = {1432-2072},
support = {81972112//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: The incidence of osteoporosis is increased in Alzheimer's disease (AD). The pathogenesis of AD with osteoporosis is still unknown, there is no ideal treatment as yet for it. 7,8-Dihydroxyflavone (7,8-DHF), a functional brain-derived neurotrophic factor (BDNF) mimetic, shows therapeutic potential for neurological and orthopedic disorders.

OBJECTIVES: This research investigated the molecular mechanisms by which 7,8-DHF mitigates bone loss and cognitive dysfunction in osteoporotic AD mice.

METHODS: Micro-CT analysis quantified bone loss in AD mice. The Morris water maze (MWM) assessed mouse cognitive function, and immunohistochemical analysis measured Aβ plaque deposition. qPCR and Western blotting measured expression levels of APP, Aβ42, TRKB, and FOXO3a in osteoblasts isolated from femoral bone marrow mesenchymal stem cells (BMSCs) and brain tissue. ELISA determined the levels of IL-1β, IL-6, osteocalcin (OCN), fibroblast growth factor 23 (FGF23) and sclerostin. For in vitro experiments, osteoblast differentiation was monitored in MC3T3-E1 cells co-cultured with Aβ42, with concurrent measurement of TRKB, AKT, and FOXO3a expression. The efficacy of 7,8-DHF against bone loss and osteoblast differentiation was systematically evaluated.

RESULTS: Cognitive impairment and bone loss manifested in APP/PS1 mice. 7,8-DHF treatment ameliorated bone mass reduction, decreased Aβ42 expression in bone tissue, and enhanced TRKB expression. Concurrently, 7,8-DHF improved cognitive function and accelerated clearance of [¹²⁵I]-Aβ42 from the brain. In in-vitro, Aβ42 increased inflammatory cytokine levels, suppressed TRKB expression, and impaired osteoblast differentiation. 7,8-DHF reduced the levels of AKT and pFOXO3a by TRKB.

CONCLUSION: 7,8-DHF could alleviate bone mass loss in AD mice by regulating the TRKB/AKT/FOXO3a pathway. This finding provides new ideas for the treatment strategy of AD with osteoporosis and is beneficial to the health of the elderly.},
}

@article {pmid41350162,
year = {2025},
author = {Rosenberg, PB and Amjad, H and Burhanullah, H and Nowrangi, M and Vandrey, R and Pierre, MJ and Outen, JD and Schultz, M and Marano, C and Agronin, M and Wilkins, JM and Harper, D and Laffaye, T and Reardon, E and Turner, K and Ozonsi, R and Drury, M and Nguyen, A and Hasoğlu, T and Cromwell, J and Leoutsakos, JM and Forester, BP},
title = {A Randomized Controlled Trial of the Safety and Efficacy of Dronabinol for Agitation in Alzheimer's Disease.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.10.011},
pmid = {41350162},
issn = {1545-7214},
abstract = {IMPORTANCE: Agitation in Alzheimer's disease (AD) is a great source of distress for patients and caregivers and a major public health burden. Current treatments are only modestly effective and many have safety issues including mortality risk. Novel therapeutic options are needed. There is preliminary evidence for the safety and efficacy of dronabinol (tetrahydrocannabinol, THC) for agitation in AD.

OBJECTIVE: Assess the safety and efficacy of dronabinol (THC) to decrease agitation in AD.

DESIGN: THC-AD was a 3-week randomized parallel double-blind placebo-controlled clinical trial, conducted between 2017 and 2024.

SETTING: 5 inpatient and outpatient academic clinical research centers in the Eastern U.S.

PARTICIPANTS: Volunteer sample of 75 participants meeting inclusion criteria for agitation of AD (International Psychogeriatric Association Provision Criteria) with Neuropsychiatric Inventory Clinician Version Agitation or Aggression (NPI-C A/A) domains total score of 4 or greater. Major exclusion criteria included seizure disorder, delirium, and non-AD dementia.

INTERVENTIONS: 3 weeks dronabinol vs. placebo titrated up to target dose of 10 mg daily in divided twice-daily.

MAIN OUTCOMES AND MEASURES: Prespecified co-primary agitation outcomes were the Pittsburgh Agitation Scale (PAS) and NPI-C A/A total score.

RESULTS: The majority of participants were female and were taking concomitant psychotropic medications (antidepressants and antipsychotics) at baseline. Study participants were moderately agitated at baseline, were diverse in ethnic background (9% Black, 11% Hispanic/Latina/Latino), and had severe cognitive impairment evidenced by MMSE or SIB-8. 84% completed the 3-week trial. Dronabinol decreased agitation on both primary outcomes greater than placebo to a clinically relevant extent. The fitted between-arm difference in PAS decline/week was -0.74 (SE 0.3, p = 0.015, effect size = 0.53) and for NPI-C A/A the decline was not significant at -1.26 (SE 0.67, p = 0.094, effect size = 0.36). No secondary outcomes differed between treatment arms including sleep, activities of daily living, Cohen-Mansfield Agitation Inventory (CMAI), cognition, intoxication, or use of 'as-needed' lorazepam or trazodone. Dronabinol treatment was not associated with greater intoxication nor with other adverse events (AEs) except for somnolence.

CONCLUSIONS AND RELEVANCE: Adjunctive dronabinol treatment was safe and effective for treating agitation in AD.

CLINICAL TRIALS REGISTRATION: NCT02792257.},
}

@article {pmid41349452,
year = {2025},
author = {Rossiter, K},
title = {Despite all our rage: An autoethnographic analysis on the role of shared affect in dementia caregiving relationships.},
journal = {Social science & medicine (1982)},
volume = {389},
number = {},
pages = {118802},
doi = {10.1016/j.socscimed.2025.118802},
pmid = {41349452},
issn = {1873-5347},
abstract = {Using an autoethnographic approach, this paper explores the phenomenon of shared rage between Alzheimer's patients and their informal family caregivers. Unlike previous analyses regarding dementia care, this work understands that rage within caregiving relationships is both dynamic and productive. Drawing broadly from social scientific studies regarding emotional labour and "feeling work," this work argues that Alzheimer's sufferers and their informal caregivers form two halves of a dyad, each of whom may use rage as a form of protection against loss of relational identity and pursuant grief, and to demand humane and dignified treatment from broken formal care systems. This individual rage simultaneously offers a point of connection between both halves of the caregiving dyad, which is otherwise torn asunder by interpersonal manifestations of the disease. Ultimately this paper argues for a brave, curious and compassionate response to caregiving dyads in which experiences of rage are not stigmatized, minimized or medicalized. Rather, this analysis suggests that experiences of anger are recognized as an often-excruciating form of emotional labour necessitated by an insidious disease and inadequate formal care systems.},
}

@article {pmid41349262,
year = {2025},
author = {Qi, L and Lin, L and Zheng, J and Liu, X and Liu, X and Chen, Z and Liu, L},
title = {Liraglutide improves cognitive function by reducing amyloid-beta peptide accumulation and inhibiting inflammation in 5 × FAD mice.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaf265},
pmid = {41349262},
issn = {1758-535X},
abstract = {Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive memory decline. The increasing prevalence of AD has attracted considerable attention globally. The glucagon-like peptide-1 analog, liraglutide, a drug widely used in the treatment of type 2 diabetes, has shown promising neuroprotective effects in AD, including enhancing neuronal survival, reducing amyloid beta protein accumulation, improving synaptic plasticity, and reducing tau protein hyperphosphorylation. However, its potential impact on cognitive function remains unclear. We evaluated the effects of liraglutide (25 nmol/day for 8 weeks) on the cognitive ability of 12-month-old 5 × familial Alzheimer's disease (FAD) mice. The Morris water maze test was used to evaluate the spatial learning ability of mice. Histological evaluations were performed by Nissl staining and transmission electron microscopy. Neuroinflammation was detected by double immunofluorescence staining and enzyme-linked immunosorbent assay. Protein expression in the cortex and hippocampal was detected by immunohistochemistry and Western blotting. The spatial cognitive ability improved in 5 × FAD mice after liraglutide administration and was associated with an increased number of pyramidal cells in the cortex and hippocampus. Liraglutide also alleviated ultrastructural changes in the chemical synapses and reduced both local and systemic inflammation in AD mice. Furthermore, liraglutide reduced amyloid β protein expression, which may be associated with the regulation of nuclear factor kappa B/beta-secretase 1 pathways in AD mice. The potential of liraglutide to improve the cognitive function in AD mice offers an effective pharmacological approach for treating neurodegenerative diseases.},
}

@article {pmid41347369,
year = {2025},
author = {Yang, J and Deng, Y and Qin, S and Chen, Z and Lu, Y and Ji, S and Hang, T and Song, M},
title = {An aggregation-induced emission-active theranostic agent for selectively detecting and intervening pathological Tau protein.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5tb01783a},
pmid = {41347369},
issn = {2050-7518},
abstract = {The accumulation of Tau aggregates is commonly linked with various neurodegenerative diseases, such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Notwithstanding substantial investments in the development of clinical strategies for effective intervention, traditional design paradigms are predominantly confined to molecules featuring either a solitary function or single-dimensional mode of intervention, ignoring the necessity of personalized and precise medicine. Herein, we design and synthesize a dual-functional aggregation-induced emission-active agent to serve as both a fluorescent probe for the imaging of pathological Tau and a modulator for intervention. This amphiphilic theranostic agent, named TPE-P9, is prepared via a one-pot Michael reaction between hydrophobic maleimide-modified tetraphenylethylene (TPE-Mal) and a hydrophilic cysteine-modified Tau-targeting peptide (CKVQIINKK). Microscale thermophoresis measurement and in vitro fluorescence analysis demonstrate that TPE-P9 exhibits specific binding affinity (Kd = 4.46 µM) and high selectivity towards Tau fibrils, featuring a pronounced low background interference, which is superior to the classical amyloid protein probe thioflavin T (ThT). At the living cellular level, TPE-P9 is capable of readily imaging endogenic pathological Tau to distinguish normal neurons from the lesional neurons in situ, and the staining consequence is almost consistent with that of ThT. On the other hand, as a modulator, TPE-P9 can potently protect neurons from cytotoxic Tau-induced apoptosis both by inhibiting aberrant post-translational modification-induced Tau self-assembly and by blocking the produced pathological Tau propagation, enhancing cell viability by 35.4%. These findings offer valuable insights for the development of innovative image-guided therapeutic strategies for targeted tauopathies treatment.},
}

@article {pmid41346709,
year = {2026},
author = {Liu, S and Semyachkina-Glushkovskaya, O and Yu, T and Ilukov, E and Rafailov, E and Sokolovski, S and Kurths, J and Zhu, D},
title = {Neuro-lymphaphotonics opens new horizons of the future technologies for the therapy of brain diseases.},
journal = {Theranostics},
volume = {16},
number = {2},
pages = {776-793},
pmid = {41346709},
issn = {1838-7640},
mesh = {Humans ; *Brain Diseases/therapy ; Animals ; Brain ; *Low-Level Light Therapy/methods ; *Lymphatic Vessels/radiation effects ; Blood-Brain Barrier ; },
abstract = {Pharmacological treatment of brain diseases is hampered by the blood-brain barrier that prevents the vast majority of drugs from entering the brain. For this reason, the pharmaceutical industry is reluctant to invest in the development of new neurotropic drugs. Even if effective pharmacological strategies for the treatment of brain diseases will be found, it will take 10-15 years between the emergence of an idea and the introduction of a drug to the market. This creates priority for the development of neuro-lymphaphotonics based on the development of promising non-pharmacological strategies for managing functions of the meningeal lymphatic vessels (MLVs). MLVs play a crucial role in the removal of toxins and metabolites from brain as well as in regulation of brain homeostasis and its immunity. Since MLVs are located on the brain surface, light penetrating the skull easily reaches MLVs and affects their functions. Therefore, MLVs are an ideal target for photobiomodulation (PBM). The pioneering studies have shown that PBM of MLVs is a promising strategy for the treatment of a wide range of neuropathology, including Alzheimer's or age-related brain diseases, brain tumor, intracranial hemorrhage, brain damages caused by diabetes. It has recently been discovered that sleep enhances the therapeutic effects of PBM and is a "therapeutic window" in overcoming the limitations of PBM in the elderly. Considering that the PBM technologies are non-invasive and safe with commercially viable possibilities (portability and low cost), neuro-lymphaphotonics open up promising prospects for the development of future technologies for the effective therapy of brain diseases.},
}

Humans
*Brain Diseases/therapy
Animals
Brain
*Low-Level Light Therapy/methods
*Lymphatic Vessels/radiation effects
Blood-Brain Barrier

@article {pmid41345983,
year = {2025},
author = {Abi-Ghanem, C and Opiela, AK and Paul, AS and Comito, ML and Hao, L and Martino, G and Kyaw, NR and Salinero, AE and Mansour, FM and Kelly, RD and Mutahi, AM and Sura, A and Thrasher, CA and Groom, EA and Batchelder, MR and Zuloaga, KL},
title = {Loss of ovarian hormones is detrimental in early disease stages of mouse models of Alzheimer's disease and multi-etiology dementia.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-025-00795-4},
pmid = {41345983},
issn = {2042-6410},
support = {A2022001F//Bright-Focus Foundation/ ; 908878//American Heart Association/ ; 25PRE1374600//American Heart Association/ ; R01 NS110749/NS/NINDS NIH HHS/United States ; U01 AG072464/AG/NIA NIH HHS/United States ; AARG-21-849204/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Up to 80% of Alzheimer's disease (AD) patients suffer from brain vascular damage resulting in multi-etiology dementia (MED). Sex is a well-known risk factor for dementia; out of three AD patients two are women. 17β-estradiol, a predominant ovarian hormone in woman before menopause, is known to have beneficial effects on the cerebrovasculature, neuroinflammation and neuroprotection. Here, we investigated the consequences of the loss of ovarian hormones caused by surgical menopause (ovariectomy) on AD and MED.

METHODS: The App[NL-F] knock-in mice were used to model AD. At about 5.5 months of age, a stage corresponding to early disease pathology, female App[NL-F] mice were subjected to ovariectomy (OVX) or sham surgery (Intact) and left to recover for 3 weeks to clear any endogenous gonadal hormones. In half of the mice from each group, MED was modeled using chronic cerebral hypoperfusion (unilateral carotid artery occlusion), a model of vascular contributions to cognitive impairment and dementia (VCID). Control animals (AD only model) received sham surgery. Mice were then subjected to a battery of behavioral tests before being euthanized and brains were collected to assess pathology.

RESULTS: We found that loss of ovarian hormones impairs spatial learning and memory, impairs activities of daily living, and affects underlying pathology including compromising microglial response. Some of these effects were exacerbated by cerebral hypoperfusion (VCID).

CONCLUSIONS: These results shed light on the effects of ovarian hormone loss after surgical menopause in female mouse model of AD and MED in order to better understand sex-specific risk factors.},
}

@article {pmid41345807,
year = {2025},
author = {Lawrence, JM and Dampier, W and Mell, JC and De Souza, DR and Schardien, K and Yeakle, K and Barnett, RJ and Sen, B and Ahmed, A and Bouchard, M and Wigdahl, B and Nonnemacher, MR},
title = {Inflammatory microglia signals drive A1-like polarization of astrocytes even in the presence of HIV-1 Tat.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {251},
pmid = {41345807},
issn = {1559-1182},
support = {NS089435/NS/NINDS NIH HHS/United States ; MH079785/MH/NIMH NIH HHS/United States ; },
mesh = {*Astrocytes/metabolism/pathology/drug effects ; Humans ; *Microglia/metabolism/pathology/drug effects ; *tat Gene Products, Human Immunodeficiency Virus/metabolism/pharmacology ; *Inflammation/pathology/metabolism ; Blood-Brain Barrier/metabolism/pathology/drug effects ; *Signal Transduction/drug effects ; *Cell Polarity/drug effects ; *HIV-1/metabolism ; Endothelial Cells/metabolism/drug effects ; Cells, Cultured ; },
abstract = {In the context of neurodegeneration, activated microglia facilitate inflammation via secretion of TNF-α, IL-1α, and C1q. Astrocytes exposed to this signaling array polarize to a reactive inflammatory phenotype, termed A1 or A1-like. Astrocytes are essential for neuronal survival, synaptic support, and blood-brain barrier (BBB) function, but A1-like astrocytes upregulate inflammatory gene expression, downregulate neurotrophic factors, and secrete neurotoxic signals. The consequences of A1-like polarization on BBB function are unknown but may have etiological implications for some diseases. Frequently identified by upregulation of complement component 3 (C3), A1-like astrocytes have been characterized in neurodegenerative disorders like Alzheimer's disease, with polarization correlated with disease progression and severity. However, the role of A1-like astrocytes in neurodegeneration associated with chronic viral infections, like HIV-1-associated neurocognitive disorder (HAND), remains unclear. An in vitro system using primary human astrocytes, as well as a BBB model featuring primary human brain microvascular endothelial cells (BMECs) co-cultured with astrocytes, was used to elucidate cellular and molecular consequences of chronic astrocyte activation. As measured by whole transcriptome analysis and protein expression assays, repeated treatment with TNF-α, IL-1α, and C1q induced A1-like polarization of astrocytes both in monoculture and in a BBB model, resulting in increased secretion of pro-inflammatory signals. No substantial change to BBB permeability was observed. In contrast, exposure to HIV-1 viral protein Tat did not independently induce A1-like polarization. Ongoing investigations into the effect of astrocyte polarization on BBB integrity and treatment with pathogenic proteins may provide insights into the role of neurotoxic astrocytes in neurovirologic pathologies.},
}

*Astrocytes/metabolism/pathology/drug effects
Humans
*Microglia/metabolism/pathology/drug effects
*tat Gene Products, Human Immunodeficiency Virus/metabolism/pharmacology
*Inflammation/pathology/metabolism
Blood-Brain Barrier/metabolism/pathology/drug effects
*Signal Transduction/drug effects
*Cell Polarity/drug effects
*HIV-1/metabolism
Endothelial Cells/metabolism/drug effects
Cells, Cultured

@article {pmid41345718,
year = {2025},
author = {Platen, M and Gläser, E and Dahling, V and Gesell, D and Hauptmann, M and Horenkamp-Sonntag, D and Koller, D and Kubat, D and Marschall, U and Riederer, C and Scheibner, H and Schroth, J and Swart, E and Michalowsky, B},
title = {Regional disparities of antidementia drug treatment in Germany: what can we learn for the new generation of Alzheimer's therapies.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01902-8},
pmid = {41345718},
issn = {1758-9193},
abstract = {BACKGROUND: Current antidementia drugs can temporarily slow cognitive decline in Alzheimer's disease but are underused. Regional and socioeconomic disparities, including limited specialist access in rural or deprived areas, may exacerbate inequities and challenge the rollout of emerging disease-modifying therapies. This study aimed to evaluate associations between regional contextual factors and antidementia drug prescription (AD-Rx) among newly diagnosed people living with Alzheimer's disease (PlwAD) in Germany and to identify spatial clustering of prescribing patterns.

METHODS: This study analyzed anonymized claims data from three statutory health insurers for 53,753 PlwAD who received their first diagnosis between January 2020 and December 2022. Regions, defined by three-digit postal codes (ZIP3, n = 576), were categorized by the German Index of Socioeconomic Deprivation (GISD) quintiles and Degree of Urbanization (urban, suburban, rural). Multilevel logistic regression with random intercepts for ZIP3 was used to assess associations between receiving AD-Rx (dichotomous) and urbanization and deprivation, adjusting for age, sex, the Charlson Comorbidity Index, the long-term care level and the year of diagnosis. Global Moran's I was used to evaluate large-scale spatial clustering, and regional Moran's I was calculated to detect regional hotspots and coldspots.

RESULTS: Overall, 64% of PlwAD received at least one AD-Rx. Rural residency was associated with slightly lower odds of receiving AD-Rx compared to urban areas (OR 0.92; 95%CI 0.87-0.98; p = 0.010), whereas deprivation was not. Interaction models demonstrated that an increased deprivation further reduced AD-Rx odds in rural areas (OR per GISD unit = 0.98; 95% CI 0.96-0.99; p = 0.024). Global Moran's I revealed no significant large-scale clustering (I = 0.011; p = 0.613), but regional analysis identified several regional hotspots (high-high clusters) predominantly in moderately deprived urban areas and coldspots (low-low clusters) in highly deprived or rural areas.

CONCLUSION: Alzheimer's patients in rural and high-deprivation regions face limited access to recommended antidementia medications. Targeted interventions, such as teleconsultations, expanding specialist outreach, and collaborative care models in underserved areas, as well as regional dementia networks and national registries, could promote the equitable delivery of current and future Alzheimer's antibody therapies. However, further qualitative and quantitative research is needed to identify the underlying regional causes of these treatment disparities.

TRIAL REGISTRATION: DRKS00031944.},
}

@article {pmid41345521,
year = {2025},
author = {Elnemais Fawzy, M and Wang, S and Palmer, P and Gatchel, J and Marshall, GA and Gagliardi, G and Vannini, P and , },
title = {Association between anosognosia and neuropsychiatric symptoms in Alzheimer's disease dementia patients.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-29569-z},
pmid = {41345521},
issn = {2045-2322},
support = {AG061083/NH/NIH HHS/United States ; },
abstract = {Anosognosia, the lack of awareness of memory decline, and Neuropsychiatric Symptoms (NPS) are prevalent and debilitating symptoms in Alzheimer's disease (AD) dementia. Understanding the coexistence of these symptoms may help guide clinical interventions and treatment strategies. This study aimed to compare NPS prevalence in patients with and without anosognosia at baseline and to assess the association between anosognosia and NPS over time. We examined patients with AD dementia enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To be included in the current study, patients had to have undergone baseline assessments and at least one subsequent follow-up evaluation. Furthermore, all patients had to have amyloid (as assessed using Positron Emission Tomography, PET), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Everyday Cognition (ECog) variables available throughout the study. Anosognosia, our exposure of interest, was determined using Ecog scores from patients and study partners. Study partners evaluated the presence or absence of 12 NPS (our outcomes of interest) using the NPI. Cox proportional hazards models, excluding patients who had any symptoms of NPS at baseline, were used to evaluate NPS onset by group (anosognosia/no anosognosia) while adjusting for age, sex, years of education, and MMSE. 112 patients with follow-up data (mean = 1 year) were included in this study. Of these, 47.3% (n = 53) had anosognosia, while 52.7% (n = 59) did not. In those with anosognosia at baseline, we observed a trend toward greater prevalence of agitation and motor symptoms. Exploratory time-to-event analysis demonstrated that the patients with anosognosia had a faster onset of apathy (HR: 2.78, 95% CI: 1.37-5.62, p = 0.01) compared to the patients without anosognosia. In this exploratory study, while there were no significant differences in frequency of NPS at baseline between the groups, patients with anosognosia demonstrated faster onset of apathy as compared to patients without anosognosia. These findings underscore the importance of longitudinal assessments and tailored interventions targeting the management of NPS in AD dementia patients with anosognosia. Further research is warranted to explain the underlying mechanisms driving these associations and to inform the development of targeted therapeutic strategies aimed at improving patient outcomes in this population.},
}

@article {pmid41344886,
year = {2025},
author = {Perovnik, M and Simončič, U and Jamšek, J and Gregorič Kramberger, M and Brumberg, J and Meyer, PT and Perani, D and Caminiti, SP and Brendel, M and Stockbauer, AC and Camacho, V and Alcolea, D and Vandenberghe, R and Van Laere, K and Ko, JH and Lee, CS and Pardini, M and Lombardo, L and Padovani, A and Pilotto, A and Ochoa-Figueroa, MA and Davidsson, A and Cháfer-Pericás, C and Álvarez-Sánchez, L and Garibotto, V and Lemstra, AW and Ferreira, D and Morbelli, SD and Tang, CC and Eidelberg, D and Trošt, M and , },
title = {Metabolic brain networks in dementia with Lewy bodies: from prodromal to manifest disease stages.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336935},
pmid = {41344886},
issn = {1468-330X},
abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, yet it remains under-recognised and misdiagnosed, which delays treatment, causes inaccurate prognosis and limits research opportunities. Imaging with 2-[[18]F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive DLB biomarker. We evaluated a multivariate, quantifiable metabolic network biomarker, termed DLB-related pattern (DLBRP), for its further clinical translation across centres and disease stages.

METHODS: We analysed demographic, clinical and FDG PET imaging data of 1180 participants from 14 tertiary centres and two multicentre datasets. We included 379 DLB, 28 mild cognitive impairment-LB (MCI-LB), 195 dementia due to Alzheimer's disease (ADD), 172 MCI-AD without α-synuclein co-pathology (MCI-AD-S-), and 73 MCI-AD with α-synuclein co-pathology (S+) patients, along with a comparative group of 333 normal controls (NCs). From the scans, we calculated the expression of DLBRP, AD-related pattern (ADRP) and Parkinson's disease-related pattern (PDRP) and compared them across groups. DLBRP scores were correlated with clinical measurements.

RESULTS: Across independent cohorts, DLBRP robustly distinguished DLB from NCs (sensitivity >89%, specificity >90%), and scores correlated with Unified Parkinson's Disease Rating Scale Part III and independently predicted Mini-Mental State Examination. DLBRP was elevated already in MCI-LB. In a small longitudinal dataset, we observed steady increases in DLBRP expression with scores exceeding the diagnostic threshold prior to dementia onset. DLBRP and PDRP discriminated DLB from ADD (sensitivity, 74%-90%; specificity, 80%). In MCI-AD groups, ADRP was expressed, whereas DLBRP and PDRP were increased only in MCI-AD-S+, although comparatively less than in MCI-LB.

CONCLUSIONS: This study demonstrates the value of DLBRP in diagnosing prodromal and manifest DLB and distinguishing them from their AD counterparts. While overlap between patterns may reflect actual co-pathology, this possibility cannot be accepted without thorough pathological confirmation. The current findings support the use of DLBRP in patient evaluation and in future trial design.},
}

@article {pmid41344825,
year = {2025},
author = {Johnson, SL and Gibbons, SR and Nielsen, CJ},
title = {Theranostics Beyond Oncology: Emerging Applications.},
journal = {Journal of nuclear medicine technology},
volume = {53},
number = {Suppl 1},
pages = {141S-143S},
doi = {10.2967/jnmt.125.271192},
pmid = {41344825},
issn = {1535-5675},
mesh = {Humans ; *Theranostic Nanomedicine/methods ; Animals ; },
abstract = {Theranostics, the combination of targeted diagnostic imaging and treatment, is rapidly expanding its role beyond oncology into various noncancerous diseases. Recent advances in radiopharmaceuticals, molecular imaging, and nanoparticle-based technologies are enabling the detection and treatment of conditions in cardiology, neurology, autoimmune, and bone marrow disorders. These innovations include targeted imaging and therapy for atherosclerosis and cardiac amyloidosis, as well as neurodegenerative disorders such as Alzheimer disease. Additionally, they encompass biomarkers such as fibroblast activation protein inhibitor and radiolabeled glucocorticoids in autoimmune and inflammatory diseases, as well as the selective ablation of diseased tissue in bone marrow conditioning. Despite the promise of these developments, several challenges must be considered, including the integration of theranostic strategies into standard practice and establishing their efficacy through robust clinical trials. This review examines the emerging nononcologic applications of theranostics, highlighting current research and future potential.},
}

Humans
*Theranostic Nanomedicine/methods
Animals

@article {pmid41341968,
year = {2026},
author = {Hong, J and An, HK and Nam, H and Choi, J and Yu, SW},
title = {Presenilin 2 regulates corticosterone-induced autophagic death of adult hippocampal neural stem cells.},
journal = {Animal cells and systems},
volume = {30},
number = {1},
pages = {35-46},
pmid = {41341968},
issn = {1976-8354},
abstract = {Chronic psychological stress is a well-known risk factor for neurodegenerative diseases including Alzheimer disease (AD), yet the underlying mechanisms remain unclear. We previously showed that chronic stress impairs adult hippocampal neurogenesis by triggering autophagic cell death of adult hippocampal neural stem (HCN) cells. Impairment of adult hippocampal neurogenesis is widely observed in the brains of human AD patients and animal models. However, it remains unknown whether stress-induced death of HCN cells is related to the pathogenesis of AD. In this study, we investigated whether the stress hormone, corticosterone (CORT) induces HCN cell death through presenilin 2 (Psen2), a gene associated with familial AD. Using CRISPR/Cas9-based knockout models and in vitro CORT treatment, we found that Psen2 expression is upregulated by CORT and Psen2 deletion prevents CORT-induced death in HCN cells. However, the Psen2 N141I mutation, despite its pathogenicity in AD, did not exacerbate CORT-induced cell death in vitro and hippocampus-dependent behavioral deficits in vivo. These findings indicate that while Psen2 is essential for stress-induced death of HCN cells, the Psen2 N141I mutation alone may not be sufficient to link chronic stress to AD pathogenesis.},
}

@article {pmid41341510,
year = {2025},
author = {Yang, J and Yang, F and Chen, G and Liu, M and Yuan, S and Zhang, TE},
title = {Receptor-mediated mitophagy: a new target of neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1665315},
pmid = {41341510},
issn = {1664-2295},
abstract = {Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.},
}

@article {pmid41341242,
year = {2024},
author = {Gutman, B and Shmilovitch, AH and Aran, D and Shelly, S},
title = {Twenty-Five Years of AI in Neurology: The Journey of Predictive Medicine and Biological Breakthroughs.},
journal = {JMIR neurotechnology},
volume = {3},
number = {},
pages = {e59556},
pmid = {41341242},
issn = {2817-092X},
abstract = {Neurological disorders are the leading cause of physical and cognitive disability across the globe, currently affecting up to 15% of the world population, with the burden of chronic neurodegenerative diseases having doubled over the last 2 decades. Two decades ago, neurologists relying solely on clinical signs and basic imaging faced challenges in diagnosis and treatment. Today, the integration of artificial intelligence (AI) and bioinformatic methods is changing this landscape. This paper explores this transformative journey, emphasizing the critical role of AI in neurology, aiming to integrate a multitude of methods and thereby enhance the field of neurology. Over the past 25 years, integrating biomedical data science into medicine, particularly neurology, has fundamentally transformed how we understand, diagnose, and treat neurological diseases. Advances in genomics sequencing, the introduction of new imaging methods, the discovery of novel molecular biomarkers for nervous system function, a comprehensive understanding of immunology and neuroimmunology shaping disease subtypes, and the advent of advanced electrophysiological recording methods, alongside the digitalization of medical records and the rise of AI, all led to an unparalleled surge in data within neurology. In addition, telemedicine and web-based interactive health platforms, accelerated by the COVID-19 pandemic, have become integral to neurology practice. The real-world impact of these advancements is evident, with AI-driven analysis of imaging and genetic data leading to earlier and more accurate diagnoses of conditions such as multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease, and more. Neuroinformatics is the key component connecting all these advances. By harnessing the power of IT and computational methods to efficiently organize, analyze, and interpret vast datasets, we can extract meaningful insights from complex neurological data, contributing to a deeper understanding of the intricate workings of the brain. In this paper, we describe the large-scale datasets that have emerged in neurology over the last 25 years and showcase the major advancements made by integrating these datasets with advanced neuroinformatic approaches for the diagnosis and treatment of neurological disorders. We further discuss challenges in integrating AI into neurology, including ethical considerations in data use, the need for further personalization of treatment, and embracing new emerging technologies like quantum computing. These developments are shaping a future where neurological care is more precise, accessible, and tailored to individual patient needs. We believe further advancements in AI will bridge traditional medical disciplines and cutting-edge technology, navigating the complexities of neurological data and steering medicine toward a future of more precise, accessible, and patient-centric health care.},
}

@article {pmid41339994,
year = {2025},
author = {Sivalingam, AM and Sureshkumar, DD},
title = {The Central Role of m6A as Epigenetic Regulator in Metabolic Disorders of Therapeutic Potential and Clinical Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {247},
pmid = {41339994},
issn = {1559-1182},
mesh = {Humans ; *Epigenesis, Genetic ; *Metabolic Diseases/genetics/therapy/metabolism ; *Adenosine/analogs & derivatives/metabolism/genetics ; Animals ; Aging/genetics ; },
abstract = {N6-methyladenosine (m6A) is the most common reversible mRNA modification, regulating fundamental cellular processes. It plays a vital role in aging and age-related diseases by influencing gene expression, RNA splicing, and stability. Growing evidence suggests that m6A modifications orchestrate key hallmarks of aging, including cellular senescence, stem cell exhaustion, and chronic inflammation factors that contribute to neurodegeneration, cardiovascular disease, and cancer. The intricate crosstalk between m6A and chromatin modifications is now recognized as a fundamental mechanism shaping age-associated epigenetic landscapes and influencing disease susceptibility. Core m6A regulators, such as METTL3, FTO, and ALKBH5, are implicated in age-related metabolic decline, neurodegeneration, and impaired tissue regeneration, making them promising therapeutic targets. Dysregulated m6A patterns are linked to aberrant RNA metabolism, protein aggregation, and synaptic dysfunction in Alzheimer's and Parkinson's diseases, while in cardiovascular and metabolic disorders, m6A modifications contribute to endothelial dysfunction, inflammation, and oxidative stress. Recent breakthroughs in computational modeling and RNA-editing technologies have revolutionized m6A research. High-precision deep-learning models (e.g., m6A-DCR) and CRISPR-based m6A editing tools provide powerful platforms to decode m6A's role in aging and disease progression. These advances pave the way for novel therapeutic strategies, offering opportunities for early diagnostics, precision medicine, and personalized interventions. Despite these promising developments, challenges remain in translating m6A-targeted therapies into clinical applications. Future research must enhance treatment specificity, minimize off-target effects, and elucidate the broader implications of m6A in aging. Advancing our understanding of m6A's functional landscape is essential for developing next-generation RNA-based therapeutics to combat aging and its associated diseases.},
}

Humans
*Epigenesis, Genetic
*Metabolic Diseases/genetics/therapy/metabolism
*Adenosine/analogs & derivatives/metabolism/genetics
Animals
Aging/genetics

@article {pmid41338979,
year = {2025},
author = {Nakamura, K and Kanou, M and Ito, S and Jimbo, T and Kouzaki, K and Nakazato, K and Nakamjima, R and Yamanouchi, K and Ueda, H and Yamana, K},
title = {Beta-nicotinamide mononucleotide attenuates creatine kinase release in Duchenne muscular dystrophy model rats.},
journal = {The Journal of veterinary medical science},
volume = {},
number = {},
pages = {},
doi = {10.1292/jvms.25-0258},
pmid = {41338979},
issn = {1347-7439},
abstract = {Beta-nicotinamide mononucleotide (beta-NMN) is a direct precursor of nicotinamide adenine dinucleotide (NAD[+]), a coenzyme essential for maintaining homeostasis in living organisms. NMN administration has attracted attention as a potential treatment for aging and age-related conditions, including diabetes, Alzheimer's disease, and chronic kidney disease. Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscle disease caused by X-linked frameshift mutations in the Dmd gene. NAD[+] levels in skeletal muscle decline in DMD pathology. In this study, we explored the therapeutic potential of NMN as an NAD[+] booster for muscular dystrophy by administering NMN to DMD rats, which exhibit severe phenotypes comparable to those of human DMD patients, for 2 months. Although NMN administration did not improve muscle function in DMD rats, it did reduce the release of creatine kinase in their blood. RNA-seq analysis revealed that NMN administration could reverse DMD-related gene expression changes associated with skeletal muscle homeostasis. These results suggest that NMN can protect skeletal muscle against degeneration in DMD and may hold therapeutic potential for DMD patients.},
}

@article {pmid41338440,
year = {2025},
author = {Zarei, O and Talebi Moghadam, M and Vastegani, SM},
title = {Machine Learning and Deep Learning in Clinical Practice: Advancing Neurodegenerative Disease Diagnosis with Multimodal Markers.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111667},
doi = {10.1016/j.brainresbull.2025.111667},
pmid = {41338440},
issn = {1873-2747},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, present major global health challenges due to their progressive and incurable nature. Early and accurate diagnosis is critical to slow disease progression and optimize therapeutic interventions, yet conventional diagnostic approaches-such as neuroimaging, cerebrospinal fluid biomarker analysis, and clinical evaluation-are often inadequate at the prodromal stage. Recent advances in artificial intelligence, particularly machine learning (ML), have provided new opportunities for precision diagnosis and treatment in neurology, using large data and multimodal biomarkers. Applications of ML to data from neuroimaging, electrophysiology, behavioral functions, speech and handwriting analysis, and molecular biomarkers have shown promising improvements in diagnostic accuracy, patient classification, and therapeutic recommendations. However, significant challenges remain, including data heterogeneity, model interpretability, population diversity, and ethical concerns surrounding patients' privacy. The purpose of this review is to examine current applications of ML in the diagnosis and management of neurodegenerative diseases through various data, highlight its strengths and limitations, and discuss future directions for using these approaches in clinical practice. We also outline emerging directions, including multimodal fusion with longitudinal data, federated and privacy-preserving learning, and the potential of explainable AI (XAI) and large language models (LLMs) in clinical decision support.},
}

@article {pmid41341247,
year = {2024},
author = {Lefkovitz, I and Walsh, S and Blank, LJ and Jetté, N and Kummer, BR},
title = {Direct Clinical Applications of Natural Language Processing in Common Neurological Disorders: Scoping Review.},
journal = {JMIR neurotechnology},
volume = {3},
number = {},
pages = {e51822},
pmid = {41341247},
issn = {2817-092X},
abstract = {BACKGROUND: Natural language processing (NLP), a branch of artificial intelligence that analyzes unstructured language, is being increasingly used in health care. However, the extent to which NLP has been formally studied in neurological disorders remains unclear.

OBJECTIVE: We sought to characterize studies that applied NLP to the diagnosis, prediction, or treatment of common neurological disorders.

METHODS: This review followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) standards. The search was conducted using MEDLINE and Embase on May 11, 2022. Studies of NLP use in migraine, Parkinson disease, Alzheimer disease, stroke and transient ischemic attack, epilepsy, or multiple sclerosis were included. We excluded conference abstracts, review papers, as well as studies involving heterogeneous clinical populations or indirect clinical uses of NLP. Study characteristics were extracted and analyzed using descriptive statistics. We did not aggregate measurements of performance in our review due to the high variability in study outcomes, which is the main limitation of the study.

RESULTS: In total, 916 studies were identified, of which 41 (4.5%) met all eligibility criteria and were included in the final review. Of the 41 included studies, the most frequently represented disorders were stroke and transient ischemic attack (n=20, 49%), followed by epilepsy (n=10, 24%), Alzheimer disease (n=6, 15%), and multiple sclerosis (n=5, 12%). We found no studies of NLP use in migraine or Parkinson disease that met our eligibility criteria. The main objective of NLP was diagnosis (n=20, 49%), followed by disease phenotyping (n=17, 41%), prognostication (n=9, 22%), and treatment (n=4, 10%). In total, 18 (44%) studies used only machine learning approaches, 6 (15%) used only rule-based methods, and 17 (41%) used both.

CONCLUSIONS: We found that NLP was most commonly applied for diagnosis, implying a potential role for NLP in augmenting diagnostic accuracy in settings with limited access to neurological expertise. We also found several gaps in neurological NLP research, with few to no studies addressing certain disorders, which may suggest additional areas of inquiry.

TRIAL REGISTRATION: Prospective Register of Systematic Reviews (PROSPERO) CRD42021228703; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=228703.},
}

@article {pmid41338025,
year = {2025},
author = {Wagdy, M and Ibrahim, AA and Yahia, AM and Maher, RM and Abo-Elwafa, AH and Salah, A and Heikal, YM},
title = {Neurobiotech innovative strategies targeting Alzheimer's disease through therapeutic micro and macroalgae potentials.},
journal = {Journal of neuroimmunology},
volume = {411},
number = {},
pages = {578821},
doi = {10.1016/j.jneuroim.2025.578821},
pmid = {41338025},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder identified by cognitive decline, memory loss, and behavioral changes, affecting approximately 50 million people worldwide. Genetic predisposition, environmental variables, and aging all play a role in the development of AD. Current therapeutic approaches primarily focus on alleviating symptoms through drugs such as donepezil and memantine. However, these treatments offer limited efficacy and may be accompanied by adverse effects. In contrast, natural therapies derived from algae present a promising alternative. Microalgae, including Chlorella and Spirulina, and macroalgae such as Fucus vesiculosus, Ecklonia cava, Sargassum, Laminaria japonica, and Fucus species, are rich in bioactive molecules having antioxidant and anti-inflammatory characteristics. These substances demonstrated potential in addressing the pathological features of AD, such as oxidative stress and neuroinflammation. Furthermore, advances in biotechnological tools like CRISPR-Cas9 gene editing are poised to enhance the efficacy of these natural therapies by targeting and modifying disease-associated genes. This review aims to bridge the fields of neurobiotechnology and marine bioresources by examining the synergistic potential of algal compounds and gene-editing strategies in combating Alzheimer's disease. Algal-derived compounds are utilized in pharmaceuticals, nutraceuticals, and dietary supplements, and may offer neuroprotective benefits that could aid in the prevention or treatment of AD.By integrating insights from molecular biology, pharmacology, and genomics, we seek to illuminate a novel, multidisciplinary framework for future therapeutic innovation.},
}

@article {pmid41338169,
year = {2025},
author = {Li, S and Li, X and Li, S and Chen, D and Xia, C},
title = {Discovery of novel hybrids of coumarin and quinoline as potential anti-Alzheimer's disease agent.},
journal = {Bioorganic & medicinal chemistry},
volume = {133},
number = {},
pages = {118499},
doi = {10.1016/j.bmc.2025.118499},
pmid = {41338169},
issn = {1464-3391},
abstract = {The multifaceted nature of Alzheimer's disease (AD) spurred growing interest in developing multi-target-directed ligands (MTDLs) for its prevention and treatment. Coumarin and quinoline scaffolds, recognized for their broad spectrum of AD-related biological activities including amyloid-β (Aβ) aggregation regulation, cholinesterase (ChE) inhibition, β-secretase 1 (BACE1) inhibition and neuroprotection, were identified as potential building blocks. Here in this study, 24 novel coumarin-quinoline hybrid compounds were rationally designed and synthesized. Inhibition studies targeting Aβ, ChE and BACE1 identified compound B8 as a promising lead compound. B8 exhibited effective binding to Aβ, and significantly attenuated Aβ-induced SH-SY5Y cell death by lowering oxidative stress and decreasing cellular apoptosis. Crucially, B8 demonstrated excellent blood-brain barrier (BBB) permeability, and intragastric administration of B8 to 7-month-old APP/PS1 transgenic mice resulted in improved cognitive function. This improvement was supported by the protection of hippocampal and cortical neurons from necrosis, attenuation of oxidative stress and inflammation in these brain regions, as well as a reduction in Aβ deposition. These findings highlight the potential of coumarin-quinoline hybrids as a novel class of AD therapeutics, with B8 emerging as a promising lead candidate warranting further investigation.},
}

@article {pmid41337426,
year = {2025},
author = {Li, J and Gao, Y and Yang, P and Guan, Z and Wang, T and Ma, G and Lei, B},
title = {Multi-Modal Feature Fusion Using Transformer for Early Alzheimer's Disease Diagnosis.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-4},
doi = {10.1109/EMBC58623.2025.11253151},
pmid = {41337426},
issn = {2694-0604},
mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; Deep Learning ; Algorithms ; Early Diagnosis ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder. Early and accurate diagnosis of AD is essential for effective treatment. However, due to the class imbalance problem, there is a significant data gap between different categories. Moreover,the data feature differences of AD are relatively small, which poses challenges for its application in the early diagnosis of AD. To tackle these problems, we propose an intelligent early AD diagnosis model based on Transformer. The deep learning diagnosis model utilizes Transformer to integrate image features and non-image features. Furthermore, it incorporates a class imbalance loss function to optimize the performance of early AD diagnosis, thereby enhancing the model's ability to recognize underrepresented classes. In order to alleviate the problem of class imbalance and test the model performance, we used stratified 5-fold cross validation to verify the model effect.Experimental results demonstrate that our model can significantly improve the accuracy of AD diagnosis, which is markedly better than traditional methods. Additionally, loss function we used more effectively mitigates the problem of class imbalance. We believe this work can effectively reduce the burden on medical staff to diagnose early AD.},
}

*Alzheimer Disease/diagnosis/diagnostic imaging
Humans
Deep Learning
Algorithms
Early Diagnosis

@article {pmid41337360,
year = {2025},
author = {Lee, HP and Arginteanu, T and Kudela, P and Wyse-Sookoo, K and Anderson, WS and Salimpour, Y},
title = {Phase-Dependent Neuromodulation in a Computational Hippocampal Model.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-4},
doi = {10.1109/EMBC58623.2025.11254724},
pmid = {41337360},
issn = {2694-0604},
mesh = {*Hippocampus/physiology ; Humans ; *Models, Neurological ; Computer Simulation ; Theta Rhythm/physiology ; Neurons/physiology ; Animals ; },
abstract = {The critical role of phase-amplitude coupling (PAC) between oscillations of differing frequencies highlights the promise of phase-dependent neuromodulation as a therapeutic strategy for various neurological conditions. In the hippocampus, theta-gamma PAC is linked to key memory processes and information transfer. Computational models avoid technical challenges in in vivo and in vitro experiments and offer a practical alternative for exploring the mechanisms behind phase-dependent effects. In this study, we built on a published CA3 hippocampal computational model implemented in the NEURON-Python environment. We used a closed-loop autoregressive (AR) forward prediction model that sampled the network's local field potential (LFP) to achieve real-time calculation of stimulus time points locked to a target phase of the theta oscillation. Our approach enabled the delivery of current injections to all neuronal populations at either the peak or the trough of the theta rhythm. Analysis of the resulting network LFP showed distinct phase-dependent changes in the theta band during stimulation. The peak-phase stimulation significantly enhanced theta-gamma coupling. Further study on a large-scale human-based model is needed to better capture these phase-dependent effects. Overall, the results underscored the importance of closed-loop stimulation systems and the potential of phase-targeted neuromodulation to influence PAC. These findings offer new avenues for treating disorders marked by disrupted oscillations, including Alzheimer's disease and other memory disorders.Clinical Relevance- This study provides investigations of the origins of neuronal oscillations and the development of a brain stimulation technique for modulating the level of oscillations, possibly contributing to the development of novel treatment methods for neurological disorders associated with abnormal oscillations..},
}

*Hippocampus/physiology
Humans
*Models, Neurological
Computer Simulation
Theta Rhythm/physiology
Neurons/physiology
Animals

@article {pmid41337282,
year = {2025},
author = {Uhm, J and Kim, HY and Choe, B and Agrawal, H and Yoon, S and Yun, JH},
title = {Smartphone Keystroke-based Cognitive Impairment Diagnostic Methodology.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-7},
doi = {10.1109/EMBC58623.2025.11253467},
pmid = {41337282},
issn = {2694-0604},
mesh = {Humans ; *Smartphone ; *Cognitive Dysfunction/diagnosis ; Male ; Aged ; Female ; },
abstract = {With the global population rapidly aging, dementia has emerged as a major public health concern. Significant efforts are being made to address the health and other problems associated with dementia. Although several advances have been made in the diagnosis and treatment of dementia, many challenges remain unresolved. Existing dementia diagnostic methods are often not performed in a timely manner due to poor accessibility, leading to delays in initiation of treatment. In this study, we propose a smartphone keystroke-based diagnostic method as a solution to overcome the limitations associated with the early diagnosis and treatment of dementia. As compared to other existing methods, the proposed diagnostic method is easier to develop and maintain, promoting commercialization and widespread use. The diagnostic method has been designed to extract language-agnostic keystroke data features from smartphone keyboard input logs. Rather than simply extracting features assessing motor skills from keystroke data or features demonstrating language usage patterns from text, this study focused on features that can assess cognitive abilities without using linguistic characteristics. Clinical trials were conducted in patients with mild cognitive impairment and early Alzheimer's dementia were conducted, and a series of experiments and validation tests were performed using the trial data. The results demonstrated that the proposed smartphone keystroke-based diagnostic method is effective in diagnosing cognitive impairment. The proposed method does not require the use of any special equipment except smartphones, which facilitates low-cost commercialization. This study presents a diagnostic method that addresses the problem of people who avoid tests for the diagnosis of dementia due to economic and psychological burdens.Clinical RelevanceThis study provides an approach for early detection of dementia using ordinary smartphone keystroke logs. The proposed method has the potential to improve the quality of life of patients with dementia. Following large-scale clinical research and the integration of more digital biomarkers, the methodology proposed in this study can potentially facilitate the development of an early diagnostic platform for dementia.},
}

Humans
*Smartphone
*Cognitive Dysfunction/diagnosis
Male
Aged
Female

@article {pmid41336985,
year = {2025},
author = {Salinas-Medina, A and Gonzalez-Mitjans, A and Toussaint, PJ and Liu, X and Evans, A},
title = {HISRON: AI-Driven GPU-Accelerated Framework for Scalable High-Resolution Neuroimaging Analysis.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-7},
doi = {10.1109/EMBC58623.2025.11253703},
pmid = {41336985},
issn = {2694-0604},
mesh = {Humans ; *Neuroimaging/methods ; *Image Processing, Computer-Assisted/methods ; *Computer Graphics ; Algorithms ; *Artificial Intelligence ; Brain/diagnostic imaging ; },
abstract = {Ultra-high-resolution imaging, particularly cellular neuroimaging, poses challenges from terabyte-scale data and computational complexity. We present HISRON (High-Resolution Scalable Neuroimaging) a GPU-accelerated framework enabling scalable multidimensional analysis, combining unsupervised learning for adaptive feature extraction, benchmarked anisotropic diffusion for noise reduction, and promptable segmentation models with a zero-shot generalization feature. Dynamic overlap-aware tiling maximizes parallelization while preserving spatial context, enabling real-time processing of complex structures. Built on NVIDIA CUDA and CuPy, the framework achieves transformative efficiency: 10x faster noise reduction and detection of 200,000 neuron centroids in 30 seconds (40% pipeline improvement). This advances integration with AI-driven segmentation/classification pipelines, overcoming bottlenecks in high-dimensional computer vision. By emphasizing scalability, our method accelerates analysis of biomedical imaging data, directly supporting translational healthcare innovations in neuroscience. The tool's adaptability underscores its potential for clinical research, enhancing precision in neuroanatomical studies and fostering discoveries in brain function and pathology.Clinical relevance-The proposed framework directly addresses critical challenges in modern clinical neuroimaging, where the analysis of high-resolution data is essential for diagnosing and monitoring neurological disorders such as Alzheimer's, Parkinson's diseases, and epilepsy. By enabling real-time processing of terabyte-scale datasets, this technology reduces delays in image interpretation, facilitating faster decision-making in time-sensitive scenarios, such as intraoperative imaging during neurosurgery or stroke assessment. The zero-shot segmentation model's adaptability ensures robust performance across heterogeneous imaging protocols, which is vital for multicenter clinical studies and personalized treatment planning. Additionally, the framework's efficiency in detecting neuron populations at scale supports large-scale neuroanatomical studies, enhancing our understanding of brain connectivity abnormalities in psychiatric and neurodegenerative conditions. By lowering computational barriers, this tool democratizes access to advanced imaging analytics, empowering clinics with limited resources to adopt precision medicine approaches. These advancements align with the growing demand for AI-driven scalable solutions to improve diagnostic accuracy, accelerate therapeutic discovery, and optimize patient outcomes in neurology and neurorehabilitation.},
}

Humans
*Neuroimaging/methods
*Image Processing, Computer-Assisted/methods
*Computer Graphics
Algorithms
*Artificial Intelligence
Brain/diagnostic imaging

@article {pmid41336397,
year = {2025},
author = {Seo, K and Hwang, J and Kim, K and Argrawal, H and Yun, JH and Yoon Kim, H},
title = {End-to-End Classification of Cognitive Impairment Using Daily-Life Gait Data.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-7},
doi = {10.1109/EMBC58623.2025.11254035},
pmid = {41336397},
issn = {2694-0604},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/physiopathology/classification ; *Gait ; Aged ; Male ; Female ; Middle Aged ; Smartphone ; Accelerometry ; *Activities of Daily Living ; Alzheimer Disease/diagnosis/physiopathology ; Wearable Electronic Devices ; },
abstract = {We investigated the feasibility of using commercial smart devices to prescreen cognitive impairments for timely intervention. A total of 125 individuals aged 50 and older were recruited from a local clinic and categorized into groups based on cognitive diagnosis: Mild Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI), and Subjective Cognitive Decline (SCD).This study focused on distinguishing individuals requiring treatment (AD and MCI) from those without cognitive impairment (SCD) using gait-related data collected from daily life. This classification task was particularly challenging, as the SCD group shares cognitive symptoms with MCI and the data was collected in non-controlled, real-world conditions.Participants used smartphones and smartwatches for one month to collect accelerometer and gyroscope data during daily activities. We preprocessed walking segments and trained a deep learning classifier to differentiate between the two groups. The model achieved an area under the curve (AUC) of 0.70, demonstrating the potential of wearable-based gait analysis for cognitive impairment detection. A sensor ablation study revealed that wrist-worn gyroscope data alone achieved a comparable AUC of 0.70, suggesting a moderate association between arm motion and cognitive impairment. The results further indicated that integrating smartphone accelerometers and smartwatch gyroscopes enhanced classification performance.This study is part of a broader multimodal research initiative that integrates gait analysis with voice recordings, phone usage patterns, and other behavioral data to improve cognitive impairment classification. Future work will explore multi-modal fusion techniques to enhance accuracy and reliability, with the long-term goal of developing accessible, real-world screening tools for early detection.},
}

Humans
*Cognitive Dysfunction/diagnosis/physiopathology/classification
*Gait
Aged
Male
Female
Middle Aged
Smartphone
Accelerometry
*Activities of Daily Living
Alzheimer Disease/diagnosis/physiopathology
Wearable Electronic Devices

@article {pmid41336106,
year = {2025},
author = {Shanmugasundaram, S and K, GG and Sinha, N},
title = {EEG Complexity Measures for Alzheimer's and Frontotemporal Dementia Classification Using Explainable Machine Learning.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-7},
doi = {10.1109/EMBC58623.2025.11253046},
pmid = {41336106},
issn = {2694-0604},
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology/classification ; *Electroencephalography/methods ; *Frontotemporal Dementia/diagnosis/physiopathology/classification ; *Machine Learning ; Male ; Female ; Aged ; Signal Processing, Computer-Assisted ; Middle Aged ; },
abstract = {This study aimed to classify patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) from healthy controls (CN) using non-linear EEG features. We explored various classification tasks, including binary classifications (CN vs. AD, CN vs. FTD, FTD vs. AD) and multi-class classifications, employing machine learning models such as XGBoost, multi-layer perceptron, k-nearest neighbors, and support vector machines. To understand the model's decision-making process, we employed explainable AI (XAI) using SHAP (SHapley Additive exPlanations) analysis. An EEG dataset of 88 subjects: 36 with AD, 29 controls, and 23 with FTD, was used. The occipital electrode O2 played a crucial role in differentiating AD from controls. In both FTD vs. AD and CN vs. FTD classifications, features from the frontal and temporal electrodes exhibited the highest importance. The results showed that XGB and MLP perform best across all classification tasks, with 100% accuracy achieved in CN vs. AD classification and area under the curve values of 0.99 for most classifiers. Distinguishing unhealthy patients (AD and FTD) from healthy controls yielded lower performance, potentially due to the differential EEG signal alterations in these conditions. The multi-class classification of AD, FTD, and controls achieved accuracy of 82%, lower than the binary classification tasks. The study proposed a novel methodology combining non-linear EEG features and machine learning models, offering the potential for improved disease detection.Clinical relevance- This study offers the potential to provide a non-invasive, efficient method for early detection and differentiation of AD and FTD from healthy controls. The ability to classify these neurodegenerative diseases using EEG, a widely accessible and cost-effective tool, could significantly aid in the timely diagnosis and monitoring of disease progression. This could lead to more personalized treatment plans and improved patient care.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology/classification
*Electroencephalography/methods
*Frontotemporal Dementia/diagnosis/physiopathology/classification
*Machine Learning
Male
Female
Aged
Signal Processing, Computer-Assisted
Middle Aged

@article {pmid41335145,
year = {2025},
author = {Banu, Z and Das, NR},
title = {Protective effects of alkaloidal fraction of Elaeocarpus angustifolius Blume against AlCl3-evoked neurotoxicity: insights from an in vivo model of Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {330},
pmid = {41335145},
issn = {1573-7365},
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Aluminum Chloride/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Male ; *Plant Extracts/pharmacology/therapeutic use ; Disease Models, Animal ; *Alkaloids/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Maze Learning/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and neuronal degeneration. Current treatments offer limited efficacy. Elaeocarpus angustifolius Blume (Rudraksha), used traditionally in Ayurveda for neurological disorders, has shown potential for cognitive health, warranting investigation in AD models. This study aimed to evaluate the neuroprotective efficacy of an alkaloid-rich fraction of E. angustifolius (EAF) in an AlCl3-induced rat model of AD. AD-like symptoms were induced by oral administration of AlCl3 (100 mg/kg) for 60 days, followed by a 30-day oral treatment with EAF (200 and 400 mg/kg). Cognitive performance was assessed using the Morris water maze, elevated plus maze, novel object recognition, and locomotor activity tests. Biochemical and molecular markers were analysed, and hippocampal histopathology was conducted. AlCl3 exposure caused significant cognitive and motor deficits, elevated Aβ1-42 and phosphorylated tau, decreased acetylcholine and dopamine, increased glutamate and NF-κB, and reduced NRF-2 expression, indicating oxidative stress and neuroinflammation. EAF treatment significantly improved behavioral outcomes, reduced Aβ1-42 and tau levels, restored neurotransmitter balance, enhanced antioxidant markers (GSH, SOD, CAT), and reduced MDA. It suppressed NF-κB and upregulated NRF-2, suggesting antioxidant and anti-inflammatory effects. Histopathological analysis confirmed hippocampal neuroprotection. EAF exhibited significant neuroprotective effects by mitigating oxidative stress, neuroinflammation, and AD-related pathologies, including amyloid accumulation and cholinergic dysfunction. These findings support the potential of EAF as a therapeutic candidate for AD prevention and management.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Aluminum Chloride/toxicity
*Neuroprotective Agents/pharmacology/therapeutic use
Rats
Male
*Plant Extracts/pharmacology/therapeutic use
Disease Models, Animal
*Alkaloids/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism/pathology
Oxidative Stress/drug effects
Maze Learning/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid41333818,
year = {2025},
author = {An, L and Zhang, J and Wang, X and Ge, Y and Sun, K and Dong, J and Wang, P and Li, W and Li, M and Hu, X and Wang, B and Yu, XA},
title = {Nanocarriers based therapy and diagnosis of brain diseases: cross the blood-brain barrier.},
journal = {Science and technology of advanced materials},
volume = {26},
number = {1},
pages = {2554048},
pmid = {41333818},
issn = {1468-6996},
abstract = {The blood-brain barrier (BBB) is the protective interface that isolates the central nervous system from circulating blood, which restricts approximately 98% of small molecule drugs and nearly all large molecules from entering the brain. Current methods to bypass the BBB, such as laser-guided interstitial thermal therapy and magnetic resonance guided focused ultrasound, are fraught with risks like impairing BBB integrity and brain damage, and are not suitable for long-term treatment. Nanocarriers have emerged as promising tools due to their ability to enhance drug delivery across the BBB while minimizing systemic toxicity. These nanocarriers leverage mechanisms including receptor-mediated, carrier-mediated, cell mediated and extra-stimuli mediated transport to improve BBB traverse and brain targeting. The review evaluates these strategies separately, discussing their potential and limitations for clinical application, and highlights recent advancements in integrating and optimizing nanocarriers utilizing synergistic strategies for the treatment and diagnosis of neurological disorders, including tumors, Alzheimer's disease, Parkinson's disease, and brain infections.},
}

@article {pmid41332987,
year = {2025},
author = {Huai, JX and Chang, EE and Zhu, YR and Ma, WL and Lv, TS and Sun, J and Zhou, XQ},
title = {Diabetic encephalopathy: metabolic reprogramming as a potential driver of accelerated brain aging and cognitive decline.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1701406},
pmid = {41332987},
issn = {2296-634X},
abstract = {Diabetic encephalopathy (DE) is a serious neurological complication of diabetes and is expressed as progressive decline in cognitive function, emotional disorders, and changes in brain structure. This review brings together the relevant evidence and demonstrates that metabolic reprogramming, the adaptive reconfiguration of the core metabolic pathway in response to hyperglycemia, is a potential driver of accelerated brain aging in DE. The main pathological characteristics are: abnormal brain insulin signaling, resulting in a decrease in neuronal glucose intake and a decrease in mitochondrial oxidative phosphorylation, oxidative stress and neuroinflammation caused by high blood sugar, in which excess reactive oxygen species (ROS), impairs mitochondrial integrity and leads to activation of microglia cells. The impaired mitophagy and the macrophages remove defects and cause the accumulation and energy collapse of the dysfunctional organelles. In addition, it promotes excessive glycolytic flux, lipolysis disorder, lactic acid accumulation, and ceramide-dependent synaptic damage. We further examine shared metabolic mechanisms between DE and neurodegenerative diseases such as alzheimer's disease (AD) and treatment strategies for pathological metabolic reprogramming including GLP-1 receptor agonists, NAD[+] boosters, and AMPK activators. This analysis laid the foundation for new intervention measures against the development of DE.},
}

@article {pmid41332414,
year = {2025},
author = {Zhao, X and Xu, Z and Wang, D and Li, T and Xu, L and Li, Z and Bai, X and Zhu, H and Liu, Y and Wang, Y},
title = {Nanotechnology-based targeted regulation of NLRP3 Inflammasome: therapeutic strategies and clinical application prospects in inflammatory diseases.},
journal = {Drug delivery},
volume = {32},
number = {1},
pages = {2580730},
doi = {10.1080/10717544.2025.2580730},
pmid = {41332414},
issn = {1521-0464},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Humans ; *Inflammasomes/metabolism ; Animals ; *Inflammation/drug therapy/metabolism ; Drug Delivery Systems/methods ; Nanotechnology/methods ; *Anti-Inflammatory Agents/administration & dosage/pharmacology ; Reactive Oxygen Species/metabolism ; Nanoparticles ; Nanomedicine/methods ; },
abstract = {The NLRP3 inflammasome plays a critical role in the onset and progression of various inflammatory diseases, making targeting its activation an important research direction for treating these conditions. Nanotechnology can effectively inhibit the activation of the NLRP3 inflammasome through several mechanisms, such as scavenging reactive oxygen species (ROS), regulating calcium ion flux, and stabilizing mitochondrial function, thereby alleviating inflammation and promoting tissue repair. Studies have demonstrated that nanomaterials exhibit promising anti-inflammatory effects in animal models, showing broad application potential, particularly in the treatment of conditions such as atherosclerosis, diabetes, and Alzheimer's disease. However, the clinical translation of nanotherapy still faces numerous challenges, including issues related to material biocompatibility, long-term safety, targeting efficiency, and controlled drug delivery. Future research should integrate targeting ligands, responsive materials, and multifunctional nanoplatforms to enhance the specificity and efficacy of treatments while minimizing side effects. Additionally, the prospects of nanotechnology in personalized treatment and clinical applications are substantial, necessitating further integration of basic research with clinical validation to expedite the clinical translation of NLRP3-targeted nanomedicines.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors
Humans
*Inflammasomes/metabolism
Animals
*Inflammation/drug therapy/metabolism
Drug Delivery Systems/methods
Nanotechnology/methods
*Anti-Inflammatory Agents/administration & dosage/pharmacology
Reactive Oxygen Species/metabolism
Nanoparticles
Nanomedicine/methods

@article {pmid41331838,
year = {2025},
author = {Kumar, N and Jangid, K and Kumar, V and Devi, B and Arora, T and Mishra, J and Kumar, V and Dwivedi, AR and Parkash, J and Bhatti, JS and Kumar, V},
title = {Investigations of 3-Hydroxy Chromone Derivatives as Multipotent Therapeutics for the Treatment of Alzheimer's Disease: In Silico and In Vitro Interventions and Fluorescence Studies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00847},
pmid = {41331838},
issn = {1948-7193},
abstract = {Chromone-based small organic molecules are designed and synthesized as putative multipotent ligands to intervene in several interlinked pathological pathways of Alzheimer's disease. The synthesized compounds were evaluated as acetylcholinesterase, monoamine oxidase, and amyloid β aggregation inhibitors using biochemical assays. Most of the compounds were found to inhibit the enzymes in a lower micromolar concentration range. In the series, two compounds, i.e., NSS-16 and NSS-18, displayed a balanced activity profile with the IC50 values of 1.77 and 1.53 μM against AChE and 2.06 and 1.51 μM against MAO-B. NSS-16 and NSS-18 showed moderate inhibitory activity against the self-induced Aβ aggregation with inhibition percentages of 17.8 and 24.0%, respectively. These compounds also showed potent antioxidant activity and formed metal chelates. In addition, the compounds were tested against SH-SY5Y neuronal cells and found to be neuroprotective and noncytotoxic. Moreover, the compounds inhibited reactive oxygen species (ROS) production up to 70% and exhibited a mixed type of inhibition in enzyme kinetic studies of AChE. These chromone derivatives showed a strong fluorescence intensity with a quantum yield of 30-50% and can be utilized in various biological studies including in vitro and in vivo assessments. Computational studies showed that the lead compounds fit well in the active cavity of enzymes and displayed thermodynamic stability for a time interval of 100 ns. Thus, these compounds displayed a multipotent activity profile and have the potential to be developed as potential therapeutics for AD.},
}

@article {pmid41330788,
year = {2025},
author = {Zimmer, JA and Sims, JR and Evans, CD and Nery, ESM and Wang, H and Wessels, AM and Tronchin, G and Sato, S and Raket, LL and Andersen, SW and Sapin, C and Paget, MA and Gueorguieva, I and Ardayfio, P and Khanna, R and Brooks, DA and Matthews, BR and Mintun, MA and , },
title = {Donanemab in early symptomatic Alzheimer's disease: results from the TRAILBLAZER-ALZ 2 long-term extension.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100446},
doi = {10.1016/j.tjpad.2025.100446},
pmid = {41330788},
issn = {2426-0266},
abstract = {BACKGROUND: Donanemab significantly slowed clinical progression in participants with early symptomatic Alzheimer's disease (AD) during the 76-week placebo-controlled period of TRAILBLAZER-ALZ 2.

METHODS: Participants who completed the placebo-controlled period were eligible for the 78-week, double-blind, long-term extension (LTE). Early-start participants were randomized to donanemab in the placebo-controlled period. Delayed-start participants (randomized to placebo) started donanemab in the LTE. Participants who met amyloid treatment course completion criteria were switched to placebo. An external control cohort comprised participants from the AD Neuroimaging Initiative (ADNI).

RESULTS: At 3 years, donanemab slowed disease progression on the Clinical Dementia Rating Scale (CDR)-Sum of Boxes (CDR-SB) in early-start participants versus a weighted ADNI control (-1.2 points; 95 % confidence interval [CI], -1.7, -0.7). Seventy-six weeks after initiating donanemab, delayed-start participants also demonstrated slower CDR-SB progression versus a weighted ADNI control (-0.8 points; 95 % CI, -1.3, -0.3). Participants who completed treatment by 52 weeks demonstrated similar slowing of CDR-SB progression at 3 years. Compared with delayed-start participants, early-start participants demonstrated a significantly lower risk of disease progression on the CDR-Global over 3 years (hazard ratio=0.73; p < 0.001). In both groups, >75 % of participants assessed by positron emission tomography 76 weeks after starting donanemab achieved amyloid clearance (<24.1 Centiloids). The addition of LTE data to prior modeling predicted a median reaccumulation rate of 2.4 Centiloids/year. No new safety signals were observed compared to the established donanemab safety profile.

CONCLUSIONS: Over 3 years, donanemab-treated participants with early symptomatic AD demonstrated increasing clinical benefits and a consistent safety profile, with limited-duration dosing.

TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04437511.},
}

@article {pmid41330635,
year = {2025},
author = {Crowe, A and Yao, Y and Newman, M and Hoxha, K and Baffic, T and Brunden, KR},
title = {HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-type Mice.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1092-25.2025},
pmid = {41330635},
issn = {1529-2401},
abstract = {A previous compound screen identified two molecules with histone deacetylase 6 (HDAC6) inhibitory activity that reduced Alzheimer's disease (AD)-like tau inclusions in a primary rat cortical neuron model seeded with AD-brain derived tau fibrils. Testing here of additional HDAC6-selective inhibitors confirmed that compounds of this type decreased neuronal tau inclusions. Moreover, HDAC6 inhibitors also reduced Parkinson's disease (PD)-like α-synuclein aggregates in primary neurons seeded with recombinant α-synuclein fibrils. Knockdown of HDAC6 expression through treatment of seeded neuron cultures with AAV harboring HDAC6-specific shRNA also resulted in a reduction of tau and α-synuclein inclusions. Multiple compounds were evaluated for their ability to inhibit brain HDAC6 in mice, and ACY-738 was found to effectively inhibit brain HDAC6 activity upon oral dosing. ACY-738 was utilized in an efficacy study in which tau and α-synuclein pathologies were induced in wild-type mice through intracerebral injections of AD-brain derived tau and α-synuclein fibrils. Groups of male and female mice first received ACY-738 in drinking water one day prior to (pre-seeding) or one week after (post-seeding) brain injections of fibrils, followed by continued dosing for an additional 3 months. A control group of fibril-injected mice received water without ACY-738. Immunohistochemical evaluations revealed that ACY-738 administration resulted in significant reductions of tau pathology in both dosing schemes. Moreover, α-synuclein pathology was significantly reduced in mice with pre-seeding ACY-738 administration, with a strong trend toward reduction after post-seeding dosing. These results suggest that HDAC6 inhibitors have potential for the treatment of AD, PD and related diseases.Significance Statement The spread and abundance of brain tau pathology correlate with AD patient cognitive status, and there are presently no approved drugs that target tau. We demonstrate that HDAC6 inhibition or knockdown reduce both tau and α-synuclein inclusions that develop in wild-type rodent neuron models. A preferred HDAC6 inhibitor, ACY-738, was identified that inhibits brain HDAC6 when administered orally to mice. This compound was examined in a wild-type mouse model that develops concurrent seeded tau and α-synuclein brain inclusions. Significant reductions of both tau and α-synuclein inclusions were observed in mice dosed with ACY-738, suggesting that HDAC6 inhibition may be a therapeutic strategy for AD, PD and related diseases.},
}

@article {pmid41330156,
year = {2025},
author = {Costa, A and Provensi, G and Titi, C and Leri, M and Bucciantini, M and Ferraroni, M and Keeton, AB and Moore, AM and Piazza, GA and Abadi, AH and Angeli, A and Supuran, CT},
title = {Exploring dual inhibitors Carbonic Anhydrases and Phosphodiesterase 5 as potential agents for treatment Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {303},
number = {},
pages = {118404},
doi = {10.1016/j.ejmech.2025.118404},
pmid = {41330156},
issn = {1768-3254},
abstract = {In this study, we report for the first time the design and evaluation of a series of compounds with potential therapeutic relevance for Alzheimer's disease (AD), able to inhibit both human Carbonic Anhydrase (hCA) isoforms most involved in this disease as well as Phosphodiesterase 5 (PDE5), using sildenafil as the structural scaffold. A total of 19 new dual-target molecules were synthesized and biologically assessed, leading to the identification of compound 8a as the most promising candidate, exhibiting potent inhibition toward both enzymatic targets. The binding interactions of three selected derivatives (6, 8a, and 10d) with hCA II were elucidated by X-ray crystallography experiments. Moreover, compound 8a demonstrated a favourable safety profile, as it did not markedly impair cell viability on differentiated SH-SY5Y at concentrations up to 100 μM and conferred protection against Aβ-induced cytotoxicity showing superior efficacy compared to the single-target reference agents acetazolamide (AAZ) and sildenafil in mitigating oxidative stress. In vivo, chronic administration of compound 8a prevented deficits in both recognition and working memory in Aβ1-42-infused mice, outperforming vehicle-treated controls. Collectively, these findings highlight the potential of dual CA/PDE5 inhibition as a novel therapeutic strategy for Alzheimer's disease.},
}

@article {pmid41316284,
year = {2025},
author = {Chen, C and Mo, M and Åkerman, M and Garcia-Ptacek, S and Xu, H and Eriksdotter, M},
title = {Dynamic associations of cholinesterase inhibitors and memantine with cognitive trajectories in individuals with Alzheimer's or mixed dementia: a real-world analysis using the quality registry SveDem.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {256},
pmid = {41316284},
issn = {1758-9193},
abstract = {BACKGROUND: Alzheimer’s disease (AD) and mixed dementia (MxD) represent major public health concerns, yet there is limited real-world evidence on the long-term associations of commonly prescribed pharmacological treatments, particularly cholinesterase inhibitors (ChEIs) and their combination with memantine. This study aims to evaluate the long-term, time-varying associations of ChEIs and memantine on cognitive decline in a large, nationwide cohort of individuals diagnosed with AD or MxD.

METHODS: This observational study utilized data from the Swedish registry for cognitive/dementia disorders (SveDem), analyzing 32,282 individuals diagnosed with AD or MxD between 2007 and 2022. Patients were followed for up to 11 years to track treatment patterns and cognitive trajectories. Initiation of ChEIs (donepezil, galantamine, or rivastigmine) or memantine within six months after an AD or MxD diagnosis and then the time-varying medications (ChEIs alone, memantine alone or memantine added on to ChEIs) within six months after each follow-up were analyzed. Linear mixed-effects model was used to assess cognitive decline measured by Mini-Mental State Examination (MMSE) score trajectories.

RESULTS: Of the 32,282 participants (mean age 78.4 years; 61% women), 78.4% initiated treatment with ChEIs alone, and 21.6% with memantine alone. Over time, prescription patterns shifted from monotherapy to combination therapy, with donepezil and galantamine more likely to achieve 1 Defined Daily Dosages (DDD) than rivastigmine users. Memantine alone users experienced a yearly cognitive decline of 1.79 MMSE points (95% CI: −1.85, −1.73). Compared with memantine users, patients on ChEIs alone declined 0.65 points less per year (95% CI: −0.59, −0.72), while those on combination therapy declined 0.19 points less per year (95% CI: −0.10, −0.28). Among ChEIs, donepezil users experienced an annual decline of 1.02 points (95% CI: −1.06, −0.98). In comparison, galantamine users declined an additional 0.05 points per year (95% CI: −0.11, 0.01), and rivastigmine users declined an additional 0.17 points per year (95% CI: −0.24, −0.11), relative to donepezil.

CONCLUSIONS: In this large cohort of patients with AD or MxD, ChEIs users alone, particularly donepezil and galantamine, showed slower cognitive decline compared to users of memantine or combination therapy users. While differences were modest, the results contribute to a better understanding of treatment trajectories in routine clinical practice.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01918-0.},
}

@article {pmid41329964,
year = {2025},
author = {Chen, M and Tang, G and Zhang, Y and Qian, ZJ},
title = {Exploring the Protective Effects of Two Alkaloids 1 and 2 from Aspergillus terreus C23-3 on Neuronal Cells by Combining Bioinformatics Prediction and Experimental Verification.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00739},
pmid = {41329964},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease that can lead to brain cell death and brain atrophy, manifested as memory loss, cognitive decline, and behavioral abnormalities. Its mechanism is complex, and there is currently no effective treatment method. The search for new therapies and natural drug candidates has become the focus of research. In recent years, marine-derived strains of Aspergillus terreus have become an important research direction for treating AD due to the unique structure and biological activity of their secondary metabolites. In this study, we investigated the potential of two alkaloids from Aspergillus terreus C23-3 in the treatment of AD through bioinformatics analysis and experimental validation. Bioinformatics analyses showed that the two alkaloids may act by modulating key targets associated with AD, especially alkaloid 2, which may exert significant therapeutic effects on AD by inhibiting glycogen synthase kinase-3β (GSK-3β) activity and reducing the level of hyperphosphorylation of Tau proteins. Molecular docking experiments showed that alkaloids 1 and 2 formed stable complexes with GSK-3β with a high affinity. Cellular experiments showed that alkaloids 1 and 2 could effectively inhibit apoptosis and injury in HT-22 cells. Further studies showed that alkaloid 2 reduced the phosphorylation level of Tau protein and attenuated oxidative-stress-induced neurological injury by inhibiting GSK-3β and its related pathways. These results suggest that alkaloid 2 has significant potential for AD therapy.},
}

@article {pmid41328628,
year = {2025},
author = {Ren, S and Singh, J and Gsteiger, S and Cogley, C and Reed, B and Abrams, KR and Dawoud, D and Owen, RK and Tappenden, P and Quinn, TJ and Bujkiewicz, S},
title = {Evaluating amyloid-beta as a surrogate endpoint in trials of anti-amyloid-beta drugs in Alzheimer's disease: a Bayesian meta-analysis.},
journal = {Journal of comparative effectiveness research},
volume = {},
number = {},
pages = {e250095},
doi = {10.57264/cer-2025-0095},
pmid = {41328628},
issn = {2042-6313},
abstract = {Aim: The use of amyloid-beta (Aβ) clearance to support regulatory approvals of drugs in Alzheimer's disease (AD) remains controversial. We evaluate Aβ as a potential trial-level surrogate endpoint for clinical function in AD. Materials & methods: Data on the effectiveness of anti-Aβ monoclonal antibodies (MABs) on Aβ and multiple clinical outcomes were identified from randomized controlled trials through a literature review. A Bayesian bivariate meta-analysis was used to evaluate Aβ as a surrogate endpoint for clinical function across all MABs and for each individual anti-Aβ MAB. The analysis for individual therapies was conducted in subgroups of treatments and by applying Bayesian hierarchical models to borrow information across treatments. Results: We identified 23 randomized controlled trials with 39 treatment contrasts for seven MABs. The surrogate relationship between treatment effects on Aβ and Clinical Dementia Rating-Sum of Boxes (CDR-SOB) across all MABs was strong: with a meaningful slope of 1.41 (0.60, 2.21) and small variance of 0.02 (0.00, 0.05). For individual treatments, the surrogate relationships were suboptimal, displaying large uncertainty. Sharing information across treatments considerably reduced the uncertainty, resulting in moderate surrogate relationships for aducanumab and lecanemab. No meaningful association was detected for other clinical outcomes, including Mini Mental State Examination and Alzheimer's Disease Assessment Scale-Cognitive Subscale. Conclusion: Although our results from the analysis of data across all MABs suggested that Aβ was a potential surrogate endpoint for CDR-SOB, individually the surrogacy patterns varied across treatments and showed no evidence of association. Bayesian information-sharing revealed moderate surrogate relationship only for aducanumab and lecanemab.},
}

@article {pmid41328259,
year = {2025},
author = {Shan, G and Cummings, J},
title = {Assessing safety and efficacy in subpopulations in Alzheimer's disease clinical trials: contextualizing representativeness.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70186},
pmid = {41328259},
issn = {2352-8737},
abstract = {UNLABELLED: Efficacy outcomes in clinical trials are based on well-powered analyes of the entire participating population. Trial populations will comprise many types of demographic and biological subgroups, including individuals of different sexes, groups of older and younger individuals, participants with or without the apolipoprotein E ε4 (APOE) genotype, ethnoracial groups, participants from urban versus rural communities, participants with lower and higher educational levels, or individuals who have or have not undergone previous therapies such as anti-amyloid monoclonal antibodies (MABs). Each subgroups is underpowered to draw definitive outcomes, and analyses can lead to inaccurate conclusions. Disciplined subgroup analysis can be hypothesis generating and can help guide drug development decision-making. The risks associated with subgroup analysis can be mitigated by using standard terminology, prespecifying outcomes of interest, stratifying randomization, conducting interaction analyses to identify confounds, and limiting the number of subgroup comparisons. Alternative efficacy and safety analyses such as the interaction test and non-inferiority analyses may yield important insights. Together, these design and analytic straegies may allow trialists to avoid spurious interpretations and derive more informative conclusions regarding the impact of therapy on subgroups in Alzheimer's disease (AD) clinical trials. Greater understanding of safety and efficacy in the subgroups participating in trials is crtically important for indicating what conclusions can be generalized if the candidate therapy is approved.

HIGHLIGHTS: Clinical trials are sized to allow well-powered conclusions based on analysis of the entire participating population.Trial populations geared to be representative of the subgroups of the older population with AD are underpowered to allow drawing confident conclusions about efficacy or safety in subgroups.Strategies such as non-inferiority analysis combined with transparent reporting of the analytic framework may facilitate understanding treatment efficacy and safety in subgroups.},
}

@article {pmid41327837,
year = {2025},
author = {Padture, A and Gupta, S and Sivaram, A and Swamy, KV},
title = {Repurposing of Potential Curcumin Derivatives Against Cyclooxygenase-2 Using In Silico Methods and Its Implications in Neurological Disorders.},
journal = {Biotechnology and applied biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1002/bab.70106},
pmid = {41327837},
issn = {1470-8744},
abstract = {Cyclooxygenase-2 (COX-2) plays a crucial role in inflammatory responses and has been implicated in neuroinflammatory processes associated with neurological disorders such as Alzheimer's disease. While selective COX-2 inhibitors (coxib class of drugs) have been developed, their use is limited by adverse effects, necessitating the exploration of alternative therapeutic approaches. This study investigates the potential of curcumin derivatives as COX-2 inhibitors and their possible therapeutic applications in neurological disorders. Previous in silico studies show various amino acids interacting with naturally occurring curcumin derivatives. We explored the potential of 2561 curcumin derivatives as COX-2 enzyme inhibitors by examining their binding affinity to the protein. Using molecular docking, we assessed their interactions with two regions of COX-2, identifying five standout compounds with powerful binding affinities. The binding energies of these compounds lie around -10.7 and -10.6 kcal/mol. To better understand how these top candidates behave in a dynamic biological environment, we ran molecular dynamics simulations focusing on their interactions with one part of the enzyme. These simulations revealed that the compounds formed stable complexes with COX-2, maintaining consistent hydrogen bonds and hydrophobic contacts throughout. RMSD and RMSF graphs exhibit greater stability of these compounds as compared to the control molecule. Finally, energy calculations confirmed that these interactions were not only stable but also energetically favorable, suggesting that several curcumin derivatives could be promising COX-2 inhibitors. This study provides valuable insights into the potential of curcumin derivatives as COX-2 inhibitors and their possible therapeutic applications in neurological disorders. The identified compounds warrant further investigation through in vitro and in vivo studies to validate their efficacy and safety as potential alternatives to current selective COX-2 inhibitors in the treatment of neuroinflammatory conditions.},
}

@article {pmid41327376,
year = {2025},
author = {Liu, LR and Li, L and Lu, LL and Fan, SJ and Liu, LZ and He, RB and Li, H and Xian, XH and Li, WB},
title = {Ceftriaxone alleviates mitochondrial damage through the inhibition of extrasynaptic NMDA receptor-mediated changes in intracellular calcium levels to improve cognitive deficits in APP/PS1 mice.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {253},
pmid = {41327376},
issn = {1758-9193},
support = {H2024206387//Natural Science Foundation of Hebei Province/ ; 81971007//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Ceftriaxone/pharmacology/therapeutic use ; *Mitochondria/drug effects/metabolism ; Mice ; *Calcium/metabolism ; *Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Presenilin-1/genetics ; Male ; Amyloid beta-Protein Precursor/genetics ; Disease Models, Animal ; Alzheimer Disease/metabolism ; Hippocampus/drug effects/metabolism ; Excitatory Amino Acid Transporter 2/metabolism/genetics ; },
abstract = {BACKGROUND: Mitochondrial dysfunction and dysregulated calcium homeostasis contribute to Alzheimer's disease (AD) pathogenesis. The extrasynaptic N-methyl-D-aspartic acid (NMDA) receptor (eNMDAR) plays a crucial role in calcium influx and subsequent signaling cascades. In individuals with AD, the reduced expression and function of glutamate transporter-1 (GLT-1) result in glutamate spillover from the synaptic clefts to the extrasynaptic region, thereby activating eNMDAR and inducing mitochondrial damage. Ceftriaxone (Cef) has been reported to ameliorate cognitive deficits in APPswe/PS1dE9 (APP/PS1) mice by upregulating GLT-1. This study aimed to explore whether Cef alleviates mitochondrial dysfunction to improve cognitive impairment and the roles of GLT-1 and eNMDAR, particularly the participation of eNMDAR-induced intracellular calcium signaling in this process.

METHODS: C57BL/6J, APP/PS1, and GLT-1-knockdown APP/PS1 mice were used. NMDA (1 mM, 2 µL per ventricle) was injected cerebroventricularly into APP/PS1 mice once to activate eNMDAR. Cef (200 mg/kg) was intraperitoneally administered for 14 days. Cognitive function was evaluated by novel object recognition, novel location recognition and Morris water maze tests. Hippocampal mitochondrial ultrastructure was observed using transmission electron microscopy. Hippocampal mitochondrial membrane potential (MMP) was detected using JC-1 staining. The expression of eNMDAR and proteins related to mitochondrial biogenesis and dynamics was evaluated by western blot. A neuron‒astrocyte coculture derived from the cerebral cortex of embryonic mice was used to evaluate the effects of Cef on eNMDAR-induced neuronal calcium influx, mitochondrial calcium accumulation and MMP loss using live-cell imaging.

RESULTS: Cef treatment attenuated hippocampal mitochondrial dysfunction, including ultrastructural damage, reduced aspect ratio, dysregulation of MMP, impaired biogenesis and dynamics, and cognitive deficits, and prevented the upregulation of eNMDAR expression in APP/PS1 mice in a GLT-1-dependent manner. These protective effects on hippocampal mitochondrial dysfunction and cognitive deficits were counteracted by eNMDAR activation. Furthermore, Cef incubation inhibited eNMDAR-mediated calcium influx in a GLT-1-dependent way and reduced MMP in primary cortical neurons. Notably, Cef incubation significantly suppressed mitochondrial calcium overload, which was mechanistically linked to the observed decline in MMP.

CONCLUSIONS: Cef treatment prevented the upregulation of eNMDAR expression and the subsequent extracellular calcium influx in a GLT-1-dependent manner, thereby reducing mitochondrial calcium loading and ultimately mitigating mitochondrial damage and cognitive deficits in APP/PS1 mice.},
}

Animals
*Ceftriaxone/pharmacology/therapeutic use
*Mitochondria/drug effects/metabolism
Mice
*Calcium/metabolism
*Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors
*Cognitive Dysfunction/drug therapy/metabolism
Mice, Transgenic
Mice, Inbred C57BL
Presenilin-1/genetics
Male
Amyloid beta-Protein Precursor/genetics
Disease Models, Animal
Alzheimer Disease/metabolism
Hippocampus/drug effects/metabolism
Excitatory Amino Acid Transporter 2/metabolism/genetics

@article {pmid41327179,
year = {2025},
author = {Eshak, D and Arumugam, M},
title = {Nanomaterials: an overview of current trends and future prospects in neurological disorder treatment.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1366},
pmid = {41327179},
issn = {1479-5876},
mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; *Nanostructures/therapeutic use/chemistry ; Animals ; Blood-Brain Barrier ; },
abstract = {The World Health Organization (WHO) has identified neurological disorders (NDs) as one of the major health concerns worldwide, resulting in high mortality rates. NDs are conditions affecting the central and peripheral nervous systems, including the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, neuromuscular junctions, and muscles. These neurological diseases include Alzheimer's disease, Parkinson's disease, glioma/brain cancer, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuroinfections, ischemic stroke, trauma, hypoxia/anoxia, and depression. Unfortunately, these disorders remain difficult to treat due to the limited ability of conventional drugs to cross the blood-brain barrier (BBB) and achieve significant pharmacological effects in the brain. There is an urgent need to develop methods that can enhance drug efficacy and bypass the BBB. The application of various nanomaterials represents a promising approach to address these neurological disorders. Drugs incorporated with nanomaterials help improve therapeutic outcomes, reduce toxicity, provide better stability, enable targeted delivery, and enhance drug loading capacity. Numerous types and morphologies of inorganic and organic nanomaterials are increasingly employed for treating NDs, including quantum dots, dendrimers, metal nanoparticles, polymeric nanoparticles, liposomes, carbon nanotubes, metal oxide nanoparticles, and micelles. Their exceptional properties such as sensitivity, selectivity, and potential to bypass the BBB make them suitable for both diagnosis and treatment of NDs. In this review article, we briefly summarize the etiology and pathophysiology of various NDs along with current literature highlighting the use of nanomaterials for treating neurological disorders.},
}

Humans
*Nervous System Diseases/therapy/drug therapy
*Nanostructures/therapeutic use/chemistry
Animals
Blood-Brain Barrier

@article {pmid41326296,
year = {2025},
author = {Welchman, AE and Kourtzi, Z},
title = {Solving the 'Goldilocks problem' in dementia clinical trials with multimodal AI.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100397},
doi = {10.1016/j.tjpad.2025.100397},
pmid = {41326296},
issn = {2426-0266},
abstract = {The development of effective therapeutics for Alzheimer's Disease and related dementias (ADRD) has been hindered by patient heterogeneity and the limitations of current diagnostic tools. New treatments have no chance of working if given to patients who cannot benefit from them. This perspective explores how advances in Artificial Intelligence (AI), particularly multimodal machine learning, can solve the 'Goldilocks problem' of identifying patients for inclusion in clinical trials and support precision treatment in real-world healthcare settings. We examine the challenges of patient stratification, grounded by a conceptual framework of identifying each person's stage and subtype of dementia. We review data from several clinical trials of Alzheimer's disease therapeutics, to explore how AI-guided patient stratification can improve trial outcomes, reduce costs and improve recruitment. Further, we discuss the integration of AI into clinical workflows, the importance of model interpretability and generalizability, and ethical imperative to address algorithmic bias. By combining AI with scientific insight, clinical expertise, and patient experience, we argue that intelligent analytics can accelerate the discovery and delivery of new diagnostics and therapeutics, ultimately transforming dementia care and improving outcomes for patients around the globe.},
}

@article {pmid41326295,
year = {2025},
author = {Au, R and Popp, Z and Low, S and Ashton, NJ and Zetterberg, H},
title = {Reinventing "N" in the A/T/N framework: The case for digital.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100395},
doi = {10.1016/j.tjpad.2025.100395},
pmid = {41326295},
issn = {2426-0266},
abstract = {Breakthroughs in biomarkers for amyloid (A), tau (T), and neurodegeneration (N) have advanced the prospects of accurate Alzheimer's disease (AD) diagnosis. However, presence of pathology does not always translate into clinical expression and there are still clear knowledge gaps as to whether someone with AD biological indicators will lead to clinically apparent disease necessary to warrant drug treatments that carry toxicity risk. Reliance on decades-old assessment tools inhibits detection and monitoring at preclinical and early disease stages when new treatments could prove most effective. Evidence has accumulated that digital measures provide accurate detection of disease at early stages. We call for a re-evaluation of the A/T/N diagnostic framework, with digital evaluation measures complementing non-AD specific neurodegeneration markers, and even potentially replacing those non-specific to AD, to provide a clinically relevant feature critical to clinical trial advances and treatment decisions. Achieving this will only be possible if further research into novel digital evaluation tools is pursued with the same support and consideration as amyloid and tau.},
}

@article {pmid41325816,
year = {2025},
author = {Farhana, F and Sultana, MA and Hia, RA and Hegde, V},
title = {Postmenopausal Sarcopenia and Alzheimer's disease: The interplay of Mitochondria, Insulin resistance, and Myokines.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106501},
doi = {10.1016/j.neubiorev.2025.106501},
pmid = {41325816},
issn = {1873-7528},
abstract = {As life expectancy increases, cognitive impairments such as Alzheimer's disease (AD) create serious problems for older adults. Women regardless of ethnicity and age group, are disproportionately affected, accounting for two-thirds of AD cases, with post-menopausal women representing over 60% of those affected. Sarcopenia, defined by gradual reduction of skeletal muscle mass, strength, and activities, is increasingly correlated with an elevated risk of cognitive decline in post-menopausal women. Menopause-related hormonal decline (particularly estrogen loss) and aging contribute to sarcopenia, characterized by muscle mitochondrial dysfunction, oxidative stress, and insulin resistance. This sarcopenia-driven reduction in muscle mass and functional capacity further reduces the production of myokines (e.g., BDNF, irisin), impairing neuronal proliferation, adult neurogenesis, and spatial learning/memory. These pathophysiological changes show a contributing link between sarcopenia and AD progression in post-menopausal women. This review is unique in that it discusses the triangular interplay between menopause, sarcopenia, and AD, offering an integrated mechanistic framework that links hormonal decline, muscle loss, and neurodegeneration. We aim to clarify the pathophysiological causes behind the muscle-brain axis and suggest viable treatment approaches to slow down sarcopenia and cognitive deterioration in postmenopausal women based on current evidence. The formulation of targeted strategies for enhancing the quality of life and lessening healthcare expenditures in this expanding population depends on the advancement of understanding this complex interconnection between menopause, sarcopenia and cognition.},
}

@article {pmid41325201,
year = {2025},
author = {Zhao, N and Wang, Y and Yang, S and Guo, W and Li, Z and Cao, H and Zhang, Z and Li, Y and Chen, D and Xia, S and Xie, Z and Qu, Y and Wu, Y and Li, J and Yi, L and Wang, G and Guo, M},
title = {Surgical Protocols for Deep Cervical Lymphovenous Anastomosis in a Rat Model: Lymph Node and Lymphatic Vessel Anastomoses.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {225},
pages = {},
doi = {10.3791/69201},
pmid = {41325201},
issn = {1940-087X},
mesh = {Animals ; *Lymphatic Vessels/surgery ; *Anastomosis, Surgical/methods ; Rats ; *Lymph Nodes/surgery ; Neck/surgery ; *Veins/surgery ; Female ; },
abstract = {Deep cervical lymphovenous anastomosis (dcLVA) has become a promising treatment strategy for Alzheimer's disease (AD), offering significant improvements compared to the current limited treatment options. However, the underlying mechanism of dcLVA remains unclear. Although clinical trials are ongoing, animal models simulating dcLVA provide a valuable tool for exploring its mechanism. This study aims to develop a standardized protocol for creating dcLVA models in animals to facilitate basic research and address clinical challenges. We describe the surgical procedures and key steps for anastomosing the deep cervical lymph node (dcLN) and its afferent lymphatic vessel (ALV) with the posterior facial vein (PFV), detailing these two distinct surgical methods: deep cervical lymph node-vein anastomosis (dcLnVA) and deep cervical lymphatic vessel-vein anastomosis (dcLaVA). Beyond promoting lymphatic drainage, the comparison of these two surgical methods also helps us to understand and explore the role of the deep cervical lymph node and deep cervical lymphatic system in the pathogenesis of AD. Overall, the complete and clear presentation of the surgical procedure and key anatomical landmarks in the rat helps to standardize the surgical protocol, which can minimize confounding factors and reduce inter-experimental variability, thus laying a solid methodological foundation for a deeper understanding of the mechanisms involved.},
}

Animals
*Lymphatic Vessels/surgery
*Anastomosis, Surgical/methods
Rats
*Lymph Nodes/surgery
Neck/surgery
*Veins/surgery
Female

@article {pmid41324859,
year = {2025},
author = {Shi, C and Dong, J and Hui, X and Xu, Z and Zhao, Z and Dong, L},
title = {Production, Mechanisms, and Therapeutic Strategies of Tryptophan Metabolites in CNS Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {226},
pmid = {41324859},
issn = {1559-1182},
support = {22XYJ0002//Xi'an Innovation Capability Strong Foundation Plan/ ; },
mesh = {Humans ; *Tryptophan/metabolism ; Animals ; *Central Nervous System Diseases/metabolism/therapy/drug therapy ; Gastrointestinal Microbiome/physiology ; },
abstract = {Tryptophan (TRP) metabolites, which are produced from TRP via three pathways-kynurenine, 5-hydroxytryptamine, and indole-are key signaling molecules of the gut-brain axis and are involved in a variety of central nervous system (CNS) disease processes, such as Alzheimer's disease, depression, and schizophrenia by orchestrating inflammatory responses, redox imbalances, neurotransmitter dynamics, mitochondrial dysfunction, and apoptotic/autophagic pathways. However, TRP metabolites exhibit bidirectional modulatory effects, combining different neuroprotective and neurotoxic substances, depending on their metabolic environment and concentration thresholds, posing significant challenges for therapeutic strategies. Therefore, it is important to modulate TRP metabolite production factors, including the regulation of key enzymes in metabolic pathways, the gut microbiota, hormones, and the disease pathology microenvironment, to promote the production of neuroprotective metabolites and inhibit neurotoxic metabolite production. In this review, we detail the influencing factors affecting TRP metabolite production, the regulatory role of TRP metabolites in CNS disorders, and therapeutic strategies related to TRP metabolites for CNS disorders. Targeting TRP metabolizing enzymes or remodeling the ecology of the gut microbiota could be a new strategy for the treatment of CNS diseases, providing a theoretical basis for future precision intervention in CNS diseases.},
}

Humans
*Tryptophan/metabolism
Animals
*Central Nervous System Diseases/metabolism/therapy/drug therapy
Gastrointestinal Microbiome/physiology

@article {pmid41323809,
year = {2025},
author = {Horgan, NG and Djurovic-Topalovic, A and Ademoye, TA and Reyes-Charles, HI and Kobayashi, N and Plascencia-Villa, G and Perry, G and Murakami, T and Fortin, JS},
title = {Epigallocatechin-3-Gallate: A potential amyloid Fibril Disaggregator of Serum amyloid A1.},
journal = {Biochemistry and biophysics reports},
volume = {44},
number = {},
pages = {102365},
pmid = {41323809},
issn = {2405-5808},
abstract = {Serum amyloid A1 (SAA1) is a 122-amino acid protein that, after cleavage, matures into a 104-amino acid form. Its N-terminus is responsible for binding high-density lipoprotein (HDL), while the C-terminus maintains its structural integrity. As an acute-phase protein, SAA1 is produced by the liver in response to acute inflammation. SAA1 is also a precursor to amyloid A (AA), and its accumulation can lead to AA amyloidosis-a condition secondary to chronic inflammation that causes tissue damage and organ dysfunction. Our study explores methods to disaggregate SAA1 fibrils isolated from the cat spleen, chicken liver, and cow liver. Specifically, we investigate the use of epigallocatechin-3-gallate (EGCG), a polyphenolic flavonoid extracted from green tea known for its anti-inflammatory and antioxidant properties, to disaggregate these fibrils. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to analyze these fibrils after treatment with 1 % DMSO and 400 μM of EGCG in 10 mM PBS (pH 7.4). The results demonstrated that EGCG effectively reduced fibril size, as confirmed by DLS characterization, with the disappearance or diminished prominence of the 10[3-4] nm peak. Additional TEM results confirmed that EGCG disaggregated amyloid-beta fibrils isolated from Alzheimer's disease brains. These findings suggest that compounds like EGCG could be valuable in treating inflammatory and neurodegenerative conditions by disaggregating amyloid fibrils.},
}

@article {pmid41323723,
year = {2025},
author = {Dewangan, B and Swain, P and Patra, S and Bodhe, PR and Kulkarni, N and Sahu, B},
title = {Synthesis and evaluation of HFIP bearing triazolo-amides as amyloid-β aggregation inhibitors and suppressors of aggregation induced neuroinflammation.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41323723},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease with biological signatures of amyloid beta (Aβ) aggregated plaques and increased levels of bio-metals like copper (Cu), zinc (Zn), and iron (Fe). Aβ-induced lysosomal membrane permeabilization is a key event in neuronal injury in AD. Aβ aggregation also modulates mitochondria membrane potential (MMP), activates interleukin 1β and NLRP3 inflammasome eventually leading to increased reactive oxygen species (ROS) production, neuronal apoptosis and mitochondrial dysfunction. Here, we report a multi-functional compound (2f) identified through structure-activity relationship study from a series of polyfluorinated triazole compounds. Compound 2f suppressed metal induced aggregation, downregulated NLRP3 inflammasome and IL-1β expression. It has maintained the lysosomal acidic pH and restored mitochondrial membrane potential. HFIP bearing triazolo amide (2f) was found to chelate with Cu(ii) and Zn(ii) selectively in the presence of a range of other physiologically relevant metals. Further, a molecular dynamics (MD) simulation study revealed 2f disrupted the aggregation via interacting with chain A of pentameric Aβ. Therefore the HFIP bearing triazole amides may serve as potential scaffolds for drug development towards the treatment of AD.},
}

@article {pmid41322563,
year = {2025},
author = {Dias, AJ and Sena Oliveira, A and Silva, AC and Braga, AL},
title = {Rational Design and Greener Synthesis of Selenylated Indolamides as Potential Anti-Alzheimer's Agents.},
journal = {ACS omega},
volume = {10},
number = {46},
pages = {56334-56348},
pmid = {41322563},
issn = {2470-1343},
abstract = {This study presents the rational design and sustainable synthesis of selenylated indolamides as potential therapeutic agents for Alzheimer's disease. Through computational approaches, including molecular docking and pharmacokinetic analyses, we identified key structural modifications that improve acetylcholinesterase inhibition, a critical target for AD treatment. We employed an environmentally benign I2/DMSO oxidation system to optimize the synthetic protocol, enabling the efficient selenylation of 27 indolamide derivatives (5a-6a) via a straightforward and practical transformation, delivering high yields of up to 99%. Importantly, the methodology proved scalable, delivering an 88% yield on a gram-scale reaction. In silico ADMET predictions using the pkCSM platform indicated that C2-selenylated indolamides possess an improved safety profile and promising pharmacokinetic properties, suggesting their potential for further drug development. In particular, compounds 5a and 5y demonstrated the best balance between reaction yield and docking score (94% and 86.17; 98% and 93.71, respectively). These findings highlight the significance of incorporating green chemistry principles alongside advanced in silico methodologies to drive innovation in drug discovery.},
}

@article {pmid41322352,
year = {2025},
author = {Liu, S and Zhao, M and Liu, Y and Yang, X and Yan, H and Xu, H and Wu, Y and Xu, Y},
title = {Comparative efficacy and safety of symptomatic therapy and disease-modifying therapy for Alzheimer's disease: a systematic review and network meta-analysis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1656906},
pmid = {41322352},
issn = {1662-4548},
abstract = {BACKGROUND: The management of Alzheimer's disease has shifted toward disease-modifying therapies aimed at delaying disease progression rather than focusing solely on symptomatic treatment. This study summarizes the latest evidence regarding the benefits and harms of anti-Alzheimer's disease drugs.

METHODS: We conducted a comprehensive review of randomized controlled trials from PubMed, Embase, Cochrane Library, Web of Science databases, and other sources up to April 2025. Two researchers independently reviewed the literature and analyzed the data. A network meta-analysis was performed using Review Manager version 5.3 and Stata version 18.0 to calculate mean differences (MDs) and 95% confidence intervals (CIs) for direct and indirect comparisons. Treatment efficacy was evaluated using the Surface Under the Cumulative Ranking Curve (SUCRA). Bias was assessed using the Revised Cochrane Risk of Bias Tool version 2.0, and publication bias was analyzed with funnel plots.

RESULTS: The network meta-analysis included 23 randomized controlled trials with 16,010 participants, evaluating nine pharmacological interventions ranging from traditional symptomatic therapies to four United States Food and Drug Administration- and National Medical Products Administration-approved disease-modifying therapies, notably anti-amyloid beta monoclonal antibodies. Aducanumab significantly improved ADAS-cog scores compared with placebo (MD -5.97, 95%CI -10.33, -1.61; SUCRA: 93.0%) and demonstrated notable improvements in ADCS-ADL scores (MD 4.99, 95%CI 2.27, 7.72; SUCRA: 98.6%). Memantine ranked highest for neuropsychiatric symptoms (SUCRA: 80.8%). Aducanumab also had the highest SUCRA for CDR-SB (91.5%) and showed moderate superiority in MMSE scores (MD 3.55, 95%CI 1.35, 5.75; SUCRA: 98.2%).

CONCLUSION: Symptomatic treatments, especially memantine for neuropsychiatric symptoms, remain effective. However, the network meta-analysis indicates that, for patients with mild cognitive impairment or mild Alzheimer's disease, aducanumab demonstrates the greatest potential for cognitive and clinical improvement (MMSE, ADAS-cog, ADCS-ADL), despite associated risks such as adverse events and amyloid-related imaging abnormalities linked to disease-modifying therapies. Lecanemab provides moderate benefits, while donanemab appears less effective. Thus, clinicians should apply disease-modifying therapies cautiously and individually, carefully balancing potential risks and benefits for each patient.

PROSPERO [CRD42025637730], https://www.crd.york.ac.uk/PROSPERO/.},
}

@article {pmid41322300,
year = {2025},
author = {Domínguez-Fernández, C and Kumar, A and Kumar, R and Darreh-Shori, T},
title = {From heart to brain: cognitive potential of propranolol and diltiazem through cholinergic enhancement via butyrylcholinesterase inhibition.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1694610},
pmid = {41322300},
issn = {1663-9812},
abstract = {BACKGROUND: Butyrylcholinesterase (BChE) has emerged as a promising therapeutic target in the treatment of Alzheimer's disease (AD), particularly in its later stages when acetylcholinesterase (AChE) activity declines. Drug repurposing offers a strategic approach to identify novel BChE inhibitors among existing FDA-approved compounds.

OBJECTIVE: This study aimed to evaluate the cholinesterase inhibitory potential of propranolol and diltiazem-two widely used cardiovascular drugs-through in silico modelling and in vitro and ex vivo enzyme-inhibition kinetic.

METHODS: Molecular docking was performed using AutoDock Vina to assess the binding affinity of propranolol and diltiazem to AChE and BChE. In vitro screening and inhibition were measured using a modified Ellman's assay with human recombinant AChE and plasma-derived BChE. Ex-vivo IC50 and Ki values were determined through kinetic analyses in pooled plasma samples, and inhibition modes were characterized using nonlinear regression models.

RESULTS: Both propranolol and diltiazem selectively inhibited BChE, with minimal activity against AChE. At 100 μM, BChE inhibition exceeded 80% for both compounds, while AChE inhibition was limited to 18% (propranolol) and 2% (diltiazem). Propranolol exhibited a Ki of 0.19 µM, comparable to the selective BChE inhibitor ethopropazine (Ki = 0.15 µM), and acted as a competitive inhibitor. Diltiazem exhibited a higher Ki of 2.3 µM. These effects were observed at concentrations within or near reported brain levels for propranolol, suggesting potential in vivo relevance.

CONCLUSION: Propranolol and diltiazem demonstrate selective BChE inhibition, with propranolol showing potency comparable to established potent BChE inhibitors. Given their established safety profiles and CNS activity, these compounds represent promising candidates for repurposing in the treatment of AD and other cognitive disorders. Further in vivo studies are warranted to explore their therapeutic potential.},
}

@article {pmid41321177,
year = {2025},
author = {Sahakian, BJ},
title = {The role of psychopharmacology and cognitive neuroscience in understanding the brain in the treatment of psychiatric disorders and neurological diseases for the benefit of society.},
journal = {Journal of psychopharmacology (Oxford, England)},
volume = {},
number = {},
pages = {2698811251397329},
doi = {10.1177/02698811251397329},
pmid = {41321177},
issn = {1461-7285},
abstract = {This perspectives piece reflects on some of the major scientific contributions in psychopharmacology, cognitive neuroscience, and public policy of Professor Barbara J. Sahakian, Commander of the Most Excellent Order of the British Empire (CBE). Her pioneering research has advanced the understanding of brain mechanisms, including neurotransmitter modulation, and psychological processes involved in cognition, emotion, and motivation, leading to novel treatments for disorders such as Alzheimer's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. She has also contributed to a better understanding of brain mechanisms underlying and psychological processes involved in these disorders. She has championed early detection of Alzheimer's disease through neuropsychological tools, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) test and contributed to identifying cognitive and neural changes in Huntington's disease gene carriers. Beyond clinical research, Sahakian has influenced public health policy through initiatives such as the UK Government Foresight Project on Mental Capital and Wellbeing and the National Institute for Health and Care Excellence guidelines on gambling-related harms. She has also led efforts in neuroethics and public engagement, co-authoring accessible science books and participating in global forums. Recent research emphasises preventative psychiatry, including lifestyle interventions, such as diet, sleep, social connection, and lifelong learning as preventive strategies for cognitive decline and mental health problems. Through interdisciplinary collaborations and mentorship, Sahakian continues to inspire the next generation of scientists to pursue innovative research for societal benefit in neuropsychopharmacology and cognitive neuroscience.},
}

@article {pmid41320930,
year = {2025},
author = {Suthar, T and Maurya, R and Sonwani, A and Upadhayay, P and Datusalia, AK and Naqvi, S and Jain, K},
title = {Nose-to-Brain Delivery of Donepezil Hydrochloride via Oleic Acid-Conjugated PAMAM G4 Dendrimers for the Treatment of Alzheimer's-Like Dementia.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c00761},
pmid = {41320930},
issn = {1543-8392},
abstract = {Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder characterized by dementia and cognitive impairments. Acetylcholinesterase (AChE) inhibitors are generally prescribed for clinical management of AD symptoms. Donepezil hydrochloride (DPZ) is a reversible, selective, and noncompetitive inhibitor of AChE recommended for the treatment of mild-to-moderate AD. However, a higher dose of this drug must be administered to achieve adequate therapeutic concentrations in the brain, leading to peripheral side effects. In the present research work, oleic acid (OA) conjugated PAMAM G4 dendrimers (OA-G4) are explored for delivering DPZ to the brain. OA was conjugated to PAMAM G4 dendrimers using EDC conjugation chemistry, and the conjugation was confirmed by nuclear magnetic resonance (NMR) and Fourier-transform infrared (FTIR) spectroscopy. DPZ was successfully loaded on the OA-G4 conjugate, and the loading and entrapment efficiency were found to be 78.59% ± 5.52% and 62.12% ± 0.67%, respectively. The drug release studies showed a faster release of DPZ from the DPZ-OA-G4 conjugate for the initial 6 h, followed by a sustained release, with 68.44% ± 1.88% of the drug released in 24 h. Cytotoxicity studies in SH-SY5Y cells demonstrated the safety and cytocompatibility of the conjugate at a wide range of concentrations. Cell internalization study revealed deep localization of the dendrimeric nanoconjugate in SH-SY5Y cells. Biodistribution studies of the OA-G4 conjugate through the intranasal route, using an IVIS whole-body live imaging system, demonstrated abundant fluorescence in the brain, indicating efficient brain targeting via nose-to-brain delivery. Neurobehavior studies in male SD rats suggested significant attenuation of AlCl3-induced cognitive decline in DPZ-OA-G4 treated animals, which was further confirmed with biochemical and histological evaluations. In conclusion, this study provides proof of concept that DPZ can be successfully targeted to the brain using ligand-conjugated dendrimeric systems via intranasal administration, a noninvasive route that enables direct nose-to-brain delivery, bypasses the blood-brain barrier, and minimizes systemic side effects.},
}

@article {pmid41319675,
year = {2025},
author = {Langbaum, JB and Bradbury, AR and Egleston, BL and McCarty Wood, E and Langlois, CM and Largent, EA and Harkins, K and Erickson, CM and Stites, SD and Oyen, E and Riviere, ME and Liu, F and Graf, A and Kim, SYH and Grill, JD and Reiman, EM and Tariot, PN and Roberts, JS and Karlawish, J},
title = {Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1.},
journal = {The lancet. Healthy longevity},
volume = {},
number = {},
pages = {100778},
doi = {10.1016/j.lanhl.2025.100778},
pmid = {41319675},
issn = {2666-7568},
abstract = {BACKGROUND: The apolipoprotein E (APOE) gene is the best established genetic risk factor for Alzheimer's disease in later life, with the ε4 allele conferring higher risk. APOE disclosure is becoming increasingly common in the clinical care of people with Alzheimer's disease and in cognitively unimpaired adults. In this study, we aimed to describe changes in measures of genetic disease knowledge and psychiatric symptoms following APOE disclosure to cognitively unimpaired adults.

METHODS: Data were collected as part of the screening phase of the global, multicentre, Alzheimer's Prevention Initiative Generation Study 1 (NCT02565511). Eligible individuals were cognitively unimpaired (Mini-Mental State Exam total score ≥24), aged 60-75 years, and psychologically pre-screened for readiness (by measures of depressive symptoms and anxiety) to receive their APOE genotype from a health-care provider. Participants were assessed before disclosure, and 2-7 days, 6 weeks, 6 months, and 12 months after disclosure. Multivariable linear and ordinal logistic regressions were used to compare changes in genetic disease knowledge, anxiety, depression, and distress by APOE4 genotype status, adjusting for key covariates, with a focus on 2-7 days after disclosure. Multiple imputation by chained equations methods was used to account for missing outcome data.

FINDINGS: The trial took place between Nov 30, 2015, and Sept 23, 2019. In total, 9496 participants (including 790 APOE4 homozygotes, 4869 heterozygotes, and 3837 non-carriers) learned their APOE genotype from a health-care provider as part of Generation Study 1 screening. 4038 (42·5%) participants were in the 65-69-year age group, 5790 (61·0%) were female, 3706 (39·0%) were male, and 8862 (93·3%) self-identified as White. Increase in genetic disease knowledge 2-7 days after disclosure was greater in APOE4 homozygotes (mean 1·19 [SD 3·95]) than in heterozygotes (0·78 [3·95], p=0·042) and non-carriers (0·29 [3·96], p=0·0002). Disease-specific distress 2-7 days after disclosure increased more in homozygotes (2·25 [6·42]) than in heterozygotes (0·53 [5·08], p<0·0001) and non-carriers (0·79 [4·95], p<0·0001). Levels of anxiety 2-7 days after disclosure increased in homozygotes (0·17 [2·95]) but decreased in heterozygotes (-0·67 [2·68], p<0·0001) and non-carriers (-0·66 [2·67], p<0·0001). There were no significant changes in depressive symptoms following disclosure for any APOE4 group. Notably, for all APOE4 groups, increases in distress and anxiety were small and did not reach predefined levels of clinical concern.

INTERPRETATION: In cognitively unimpaired, psychologically pre-screened adults, APOE disclosure by a trained health-care provider was generally safe and well tolerated, consistent with results from previous studies. To our knowledge, this is the largest study experience of APOE disclosure to date, especially for homozygotes, and is notable for the older age of participants compared with previous research. These results are timely and important given anticipated increases in APOE disclosure to guide clinical decision making once an Alzheimer's disease prevention treatment is approved for cognitively unimpaired adults or if patients' family members are interested in genetic testing. Scalable approaches for returning Alzheimer's disease risk information are critical to meeting anticipated demand. Results from this study may be useful to bolster clinical translatability of disclosure programmes.

FUNDING: The National Institute on Aging, Alzheimer's Association, Banner Alzheimer's Foundation, GHR Foundation, F-Prime Biomedical Research Initiative (FBRI), and Novartis Pharma.},
}

@article {pmid41319153,
year = {2025},
author = {Wu, CY and Chen, L and Fatima, H and Gatchel, J and Das, S and Kivisäkk, P and Arnold, SE and Dodge, HH},
title = {Combined use of plasma p-tau217, NfL, and GFAP predicts domain-specific cognitive decline in cognitively unimpaired and MCI individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70934},
pmid = {41319153},
issn = {1552-5279},
support = {P30AG062421/GF/NIH HHS/United States ; R01AG051628/GF/NIH HHS/United States ; R01AG056102/GF/NIH HHS/United States ; K01AG088184/GF/NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood ; Male ; Female ; *Cognitive Dysfunction/blood/diagnosis ; *Glial Fibrillary Acidic Protein/blood ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Aged ; Phosphorylation ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Accurate identification of individuals at risk for cognitive decline is critical for treatment planning and trial enrichment strategies. We evaluated the combined utility of plasma phosphorylated tau at threonine 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in predicting domain-specific cognitive decline.

METHODS: Participants (n = 523; 40.9% cognitively unimpaired [CU]; 59.1% mild cognitive impairment [MCI]) were from the Massachusetts Alzheimer's Disease Research Center. Cognition was assessed using the National Alzheimer's Coordinating Center Uniform Data Set. Participants were classified as high(+)/low(-) for each biomarker using Gaussian mixture models.

RESULTS: Among all participants, high p-tau217 alone [p-tau217(+)NfL(-)GFAP(-)] was associated with a steeper decline in episodic/semantic memory and processing speed compared to the all-low group (p ≤ 0.02). With the addition of high GFAP [p-tau217(+)NfL(-)GFAP(+)], steeper decline extended to most cognitive domains, including global cognition and executive function, compared to the all-low group. In CU, faster decline in global cognition and executive function was seen when all biomarkers were elevated ([p-tau217(+)NfL(+)GFAP(+)]; p ≤ 0.04).

DISCUSSION: Combined plasma biomarkers predict decline in cognitive domains vulnerable to early disease.

HIGHLIGHTS: High phosphorylated tau at threonine 217 (p-tau217) alone was associated with declines in semantic/episodic memory, whereas its combination with elevated glial fibrillary acidic protein (GFAP) predicted declines in a wider range of cognitive domains. Elevated neurofilament light chain (NfL) amplifies the cognitive decline already driven by p-tau217 and GFAP. In cognitively unimpaired individuals, subtle domain-specific cognitive declines can be detected when both core and non-core Alzheimer's disease biomarkers are used. Our finding highlights the importance of focusing on vulnerable cognitive domains during early disease where global cognition may appear stable but specific impairments can be masked within composite scores.},
}

Humans
*tau Proteins/blood
Male
Female
*Cognitive Dysfunction/blood/diagnosis
*Glial Fibrillary Acidic Protein/blood
*Neurofilament Proteins/blood
Biomarkers/blood
Aged
Phosphorylation
Neuropsychological Tests
Aged, 80 and over

@article {pmid41318982,
year = {2025},
author = {Huang, Y and Guo, Y and Zhang, H and Deng, J and Huang, Z and Chen, A and Wu, X and Lin, D and Ye, P and Chen, X and Zheng, X},
title = {Repeated Exposure to Lidocaine Induces Alzheimer's-Like Cognitive Impairment Neuropathology in Aged Mice Through BDNF-Regulated Autophagy.},
journal = {Journal of cellular and molecular medicine},
volume = {29},
number = {23},
pages = {e70970},
pmid = {41318982},
issn = {1582-4934},
support = {82171186//National Natural Science Foundation of China/ ; 82471278//National Natural Science Foundation of China/ ; 2023Y9282//The Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2023Y9315//The Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2021QH1307//Startup Fund for scientific research, Fujian Medical University/ ; },
mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; *Autophagy/drug effects ; Mice ; *Lidocaine/adverse effects ; *Cognitive Dysfunction/pathology/metabolism/chemically induced ; *Alzheimer Disease/pathology/metabolism/chemically induced ; Hippocampus/pathology/metabolism/drug effects ; Male ; Signal Transduction/drug effects ; Receptor, trkB/metabolism ; Astrocytes/metabolism/drug effects/pathology ; Disease Models, Animal ; TOR Serine-Threonine Kinases/metabolism ; *Aging/pathology ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; },
abstract = {Lidocaine is widely used for perioperative pain management, but repeated exposure may cause neurotoxicity, including neurological deficits. This study investigates mechanisms underlying cognitive decline induced by repeated lidocaine exposure. Eighteen-month-old mice received repeated clinically relevant lidocaine infusions over 3 days. Cognitive function was assessed by Morris water maze, Y-maze and open field tests. Hippocampal pathology was examined via TEM, Nissl staining, immunofluorescence for astrocyte polarisation and Aβ deposition, and western blot for tau, BDNF, TrkB, mTOR and autophagy proteins. The TrkB agonist 7,8-DHF was used to modulate BDNF/TrkB/mTOR signalling. Repeated lidocaine exposure impaired cognition and induced Alzheimer's-like hippocampal pathology, as evidenced by increased accumulation of Aβ and tau toxic proteins, along with neuronal death. It reduced BDNF expression, inhibited TrkB phosphorylation, and activated mTOR signalling, leading to autophagy inhibition and pathological protein accumulation. Lidocaine shifted astrocytes towards the neurotoxic A1 phenotype, decreasing neuroprotective A2 astrocytes and BDNF synthesis. TrkB agonist treatment restored signalling, enhanced autophagy and improved cognitive deficits and pathology. Repeated lidocaine exposure promotes A1 astrocyte increase and A2 decrease, inhibiting autophagy via the BDNF/TrkB/mTOR pathway, resulting in toxic protein deposition and Alzheimer's-like cognitive impairment.},
}

Animals
*Brain-Derived Neurotrophic Factor/metabolism
*Autophagy/drug effects
Mice
*Lidocaine/adverse effects
*Cognitive Dysfunction/pathology/metabolism/chemically induced
*Alzheimer Disease/pathology/metabolism/chemically induced
Hippocampus/pathology/metabolism/drug effects
Male
Signal Transduction/drug effects
Receptor, trkB/metabolism
Astrocytes/metabolism/drug effects/pathology
Disease Models, Animal
TOR Serine-Threonine Kinases/metabolism
*Aging/pathology
Amyloid beta-Peptides/metabolism
Mice, Inbred C57BL

@article {pmid41318018,
year = {2025},
author = {de Souza, PC and Bezerra, TPW and de Melo Rêgo, MJB and da Rosa, MM},
title = {Advances in Neurological Therapies: A Review of Clinical Trials in Alzheimer's, Parkinson's, and Multiple Sclerosis.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2025.11.025},
pmid = {41318018},
issn = {1555-7162},
abstract = {The period from 2020 to 2025 marked a pivotal juncture in the treatment of major neurological diseases, with Phase II-IV trials delivering the first compelling evidence for disease-modifying interventions in Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This narrative review provides a critical analysis of this evolving therapeutic landscape, focusing on efficacy, safety, and practical implications. Our analysis reveals unprecedented yet heterogeneous progress. In Alzheimer's disease, anti-amyloid monoclonal antibodies (donanemab, lecanemab) achieved regulatory approval, establishing a new treatment paradigm despite modest efficacy and risks of amyloid-related imaging abnormalities (ARIA). In Parkinson's disease, GLP-1 receptor agonists (lixisenatide) demonstrated the first convincing disease modification signals in Phase II trials. For multiple sclerosis, the failure of Bruton's tyrosine kinase (BTK) inhibitors contrasted with the consolidation of anti-CD20 therapies as the therapeutic standard, refined by innovations in dosing and delivery. Collectively, these findings herald a new era of disease-modifying therapy in neurology, though current gains remain limited and dependent on biomarker stratification and safety monitoring. The challenge ahead is translating these successes into accessible, sustainable clinical benefits.},
}

@article {pmid41317176,
year = {2025},
author = {Pour, FT and Saadatpour, F and Salari, A},
title = {Comprehensive and In-Depth Molecular and Pathway Studies of the Hippocampus in Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {110},
pmid = {41317176},
issn = {1573-6830},
support = {CSBI14011102//Cognitive Science and Biology Institute (CSBI)/ ; SBNGC14011101//Systems Biology and Next Generation Company (SBNGC)/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Humans ; *Hippocampus/metabolism/pathology ; Protein Interaction Maps/genetics ; *Signal Transduction/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; Male ; Gene Expression Regulation ; Female ; },
abstract = {Alzheimer's disease (AD) still lacks a conclusive treatment, largely due to an incomplete understanding of the molecular mechanisms involved. To enhance our knowledge of AD pathogenesis and identify potential therapeutic targets, this study integrates differential gene expression analysis, pathway enrichment, hub gene discovery, protein-protein interaction (PPI) clustering, and transcription factor/protein kinase regulation into a single, cohesive pipeline. This comprehensive systems-level approach moves beyond single-gene analyses to offer a broader, mechanistically focused insight into AD biology. Using RNA-seq data from the CA1 region of the hippocampus-a subregion selectively affected in early AD-we identified 1,104 differentially expressed genes (DEGs). Among the enriched pathways, "7-alpha-hydroxycholesterol" was upregulated, while "vacuolar organization" was downregulated in AD samples. Furthermore, five novel hub genes (MRPS7, RPL5, GFM1, RAD51, and ASPM) were identified within the PPI network. The first three-MRPS7, RPL5, and GFM1-along with ACO2 and MT-ATP6, are potentially linked to hereditary forms of AD due to their roles in mitochondrial function. We also discovered four collaborative clusters within the network that notably associated with the "inflammatory response", "7-alpha-hydroxycholesterol", "Mitochondrial dysfunction" and "Oxidative phosphorylation" pathways, making them promising candidates for therapeutic and diagnostic investigation due their behavioral information members. Additionally, we identified ten transcription factors (GATA2, CHD1, THRA, IRF7, ZBTB48, POLE4, ZNF219, SLC2A4RG, NR1D1, and RXRA) and one protein kinase (PRKCZ) as potential regulatory elements in AD. This study broadens our understanding of Alzheimer's disease by identifying five candidate hub genes, two functional PPI clusters, two signaling pathways, and eleven regulatory proteins, thereby laying the groundwork for future therapeutic and diagnostic developments in molecular AD research.},
}

*Alzheimer Disease/genetics/metabolism/pathology
Humans
*Hippocampus/metabolism/pathology
Protein Interaction Maps/genetics
*Signal Transduction/genetics
Gene Regulatory Networks
Gene Expression Profiling
Male
Gene Expression Regulation
Female

@article {pmid41315790,
year = {2025},
author = {Dong, D and Ahmed, W and Sagar, R and Boyd, RJ and Mahairaki, V},
title = {Mapping key mitochondrial genes in Alzheimer's disease through human tissue and iPSC derived neurons.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {42766},
pmid = {41315790},
issn = {2045-2322},
support = {RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurons/metabolism/pathology ; *Mitochondria/genetics/metabolism ; *Genes, Mitochondrial ; Oxidative Stress/genetics ; Gene Expression Profiling ; Gene Ontology ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition that has become a global health challenge due to an aging world population and no available effective treatment. Mitochondrial dysfunction plays a crucial role in the development of AD due to its critical role in neuronal survival and function. However, the specific mitochondrial genes and pathways involved in AD pathogenesis remain poorly defined. In this study, we incorporated seven AD human postmortem and three AD iPSC-derived neurons (iNs) gene expression datasets to identify mitochondria-related Differentially Expressed Genes (mitoDEGs) between AD and control. The Gene Ontology (GO) analysis is conducted to investigate the AD biological mechanisms, and a random forest model is developed to assess how well the key mitoDEGs differentiate AD and control groups. Through our analysis, we identified fourteen key mitochondria related genes that show significant dysregulation in both postmortem brain tissues and iNs derived from AD patients. These genes have strong connections to oxidative stress, indicating mitochondrial dysfunction plays a crucial role in Alzheimer's disease pathology. Our study identified the key genes and pathways as promising targets for future research and therapeutic interventions, highlighting the importance of mitigating oxidative stress and restoring mitochondrial function in AD.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Induced Pluripotent Stem Cells/metabolism/cytology
*Neurons/metabolism/pathology
*Mitochondria/genetics/metabolism
*Genes, Mitochondrial
Oxidative Stress/genetics
Gene Expression Profiling
Gene Ontology
Brain/metabolism/pathology

@article {pmid41314754,
year = {2025},
author = {Jana, MK and Swarup, V and Tripathy, S and Gupta, NM and Chatla, SS and Joshi, D and Mandal, S and Giri, A and Jana, S and Narayan, M and Maiti, SB and Das, S},
title = {Future horizons: Innovation, aging, and equity.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {427-468},
doi = {10.1016/bs.pbr.2025.08.010},
pmid = {41314754},
issn = {1875-7855},
mesh = {Humans ; *Aging ; *Precision Medicine/trends/methods ; *Neurodegenerative Diseases/therapy/diagnosis ; Artificial Intelligence ; },
abstract = {Precision medicine is on the verge of transforming the treatment of neurodegenerative diseases (NDDs) like Alzheimer's disease (AD) and Parkinson's disease (PD), in response to the intricate interactions of genetic, epigenetic, environmental, and lifestyle factors underlying disease heterogeneity. As the world's aging populations grow, with dementia cases expected to double by 2040 and the costs amounting to over €130 billion a year in Europe alone, there is an urgent need for novel strategies to stem the socioeconomic costs of NDDs. Conventional "one-drug-fits-all" strategies that depend on late-stage symptom treatment are progressively insufficient for disorders that are marked by heterogeneous molecular pathways and unpredictable clinical courses. Recent improvements in artificial intelligence (AI), multi-omics integration, and biomarker research now allow patients to be stratified into subpopulations following their genetic risk profiles, neuroimaging signatures, and fluid biomarkers (e.g., amyloid-beta, tau, α-synuclein), enabling early diagnosis and focused treatments. For example, artificial intelligence platforms such as the IHI-PROMINENT project are creating forecasting algorithms to chart disease progression and tailor treatment outcomes, and gene therapy and antisense oligonucleotides (ASOs) address precise mutations in familial AD and PD. These advances are supported by pharmacogenomics, which individualizes drug regimens according to metabolic profiles to reduce side effects and maximize efficacy. Still, translating these advances into practice has major barriers to overcome, such as large-scale biomarker validation, multi-omics standardization, and incorporating real-world evidence from digital health technologies. Aging populations only add complexity to this environment, as comorbidities like diabetes and cardiovascular diseases interact with neurodegenerative pathways, requiring system-based, holistic approaches to care. Equity is still a key challenge: differences in access to sophisticated diagnostics (e.g., PET scans, CSF examination) and expensive therapies (e.g., monoclonal antibodies, CAR-T cell therapy) threaten to worsen global health disparities. In retaliation, initiatives such as the JPND research paradigm advance remote clinical trials and telemedicine platforms for the diverse community in decentralized settings, and policies target reducing financial disincentives through risk-sharing strategies and public-private partnerships. Precision medicine in the treatment of NDDs depends on an integrated network among academia, clinics, and industry, by taking advantage of communal biobanks and AI-enabled big data analysis, for refining the drug development process and validating new targets, e.g., neuroinflammatory signaling and gut-brain axis dysfunction. Innovations, like CRISPR-mediated editing and ambient neuroimaging, have innate or potential power to personalize treatment by identifying early-stage and even pre-symptomatic patients and modulating one's lifestyle in light of genetic risk. However ethical considerations around data privacy, algorithmic bias, and informed consent for Sustained therapeutic interventions over a lifetime should guide, not lag, the transformation. With the drive toward preventive rather than delayed care, precision medicine represents a revolutionary paradigm shift in health care, and a possibility to convert NDDs from devastatingly fatal diagnoses to easily managed chronic diseases and render equitable access to innovations possible for the masses. Success will require consistent investment in translational studies, interdisciplinary training, and global regulatory harmonization to translate the promise of precision medicine into tangible improvements in the quality of life for the millions of individuals afflicted with neurodegenerative disorders.},
}

Humans
*Aging
*Precision Medicine/trends/methods
*Neurodegenerative Diseases/therapy/diagnosis
Artificial Intelligence

@article {pmid41314753,
year = {2025},
author = {Jana, MK and Mukherjee, P and Chatla, SS and Sharma, P and Mistry, J and Swarup, V and Srivastava, AK and Das, S and Gupta, NM and Ahuja, A and Samanta, S and Narayan, M},
title = {Global case studies and collaborative frameworks.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {377-426},
doi = {10.1016/bs.pbr.2025.08.013},
pmid = {41314753},
issn = {1875-7855},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/diagnosis ; *Biomedical Research ; *International Cooperation ; },
abstract = {As neurodegenerative diseases (NDDs) like Alzheimer's and Parkinson's continue to rise globally, the need for cross-border collaboration in research and treatment has never been more critical. This chapter explores prominent global case studies and collaborative frameworks that exemplify how united efforts are transforming the landscape of NDD research. By pooling expertise, data, and resources, international initiatives are accelerating discoveries in early diagnosis, biomarker identification, and personalized therapies. Highlighting landmark consortia such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n.d.), Parkinson's Progression Markers Initiative (PPMI), and emerging multi-omics collaborations, the chapter illustrates how these partnerships overcome the complexity and heterogeneity of NDDs. It delves into technological innovations like artificial intelligence, blockchain data sharing, and real-time patient monitoring, which empower researchers and clinicians to connect genetic, environmental, and lifestyle factors in a holistic manner. Ethical considerations and data privacy frameworks are underscored as pivotal to fostering trust among participants and bridging disparities between regions with varying access to precision medicine. The chapter also sheds light on successful public-private partnerships and patient-focused global networks that place individuals at the center of discovery and care. Challenges such as standardizing protocols across countries, navigating legal frameworks, and securing sustainable funding are discussed alongside future directions for expanding collaborative reach. Ultimately, this comprehensive overview conveys the unprecedented promise held by global cooperation in combating neurodegenerative diseases-offering hope for improved diagnostics, innovative treatments, and enhanced quality of life for millions worldwide.},
}

Humans
*Neurodegenerative Diseases/therapy/diagnosis
*Biomedical Research
*International Cooperation

@article {pmid41314749,
year = {2025},
author = {Priyanka, S and Manjari, T and Hemalatha, S and Ambika, S and Yılmaz, B and Aktürk, B and Arısan, ED and Kumari, A and Manojkumar, Y},
title = {Precision therapeutics for Alzheimer's disease.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {247-276},
doi = {10.1016/bs.pbr.2025.08.011},
pmid = {41314749},
issn = {1875-7855},
mesh = {Humans ; *Alzheimer Disease/therapy/genetics/drug therapy ; *Precision Medicine/methods ; Animals ; },
abstract = {Despite extensive research, Alzheimer's disease (AD) a progressive neurodegenerative disorder marked by cognitive decline, neuronal loss, and the build-up of amyloid-beta plaques and tau tangles continues to lack effective treatments. Precision medicine presents a promising shift by customizing interventions to an individual's genetic, molecular, and lifestyle profile. This chapter explores key advancements in precision therapeutics for AD, including biomarker-driven therapies, pharmacogenomics, and targeted disease-modifying agents such as monoclonal antibodies. Recent innovations, including RNA-based therapeutics, stem cell approaches, and CRISPR-mediated gene editing, are also discussed. While precision medicine holds immense promise, challenges in clinical translation, patient stratification, and regulatory pathways must be addressed. By bridging cutting-edge research with clinical applications, this chapter provides insights into the evolving landscape of individualized treatment strategies for AD.},
}

Humans
*Alzheimer Disease/therapy/genetics/drug therapy
*Precision Medicine/methods
Animals

@article {pmid41314745,
year = {2025},
author = {Fatima, S and Tiwari, S and Siddiqi, B and Quadri, SN and Abdin, MZ},
title = {Biomarkers: From early detection to treatment personalization.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {131-153},
doi = {10.1016/bs.pbr.2025.08.008},
pmid = {41314745},
issn = {1875-7855},
mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; *Precision Medicine/methods ; Early Diagnosis ; },
abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present increasing issues associated with the unavoidable aging of the world's population. These challenges are further highlighted by the socioeconomic consequences of these diseases. The identification and use of biomarkers for prompt diagnosis, careful observation, and efficient treatment approaches is essential to overcoming these obstacles. The primary methods for diagnosing neurodegenerative illnesses are invasive procedures like lumbar punctures to measure CSF fluid or functional brain imaging methods. Biomarkers for underlying proteinopathy in blood serum and cerebral fluid have been the focus of recent biological research, particularly in vivo. With their ability to provide novel pathways for early detection, illness progression tracking, and individualized treatment plans, biomarkers have become essential instruments in precision medicine. The classification of biomarkers including fluid, digital imaging, and molecular biomarkers is examined in this chapter, with an emphasis on their function in neurodegenerative diseases. In neurodegenerative illnesses and the aging brain, tau, amyloid-β, α-synuclein, and TDP-43 are commonly seen to be deposited together rather than separately. These may be disregarded, and it might be challenging to determine their clinicopathological significance. An overview of illness pathophysiology, diagnostic implications, and the most recent molecular and ultrastructural categories for neurodegenerative disorders are given in this chapter. Addressing these issues through interdisciplinary research and technological advancements will be crucial for the future of biomarker-driven precision medicine. This chapter provides an in-depth overview of the evolving landscape of biomarkers and their transformative impact on the early detection and personalized treatment of neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/therapy/metabolism
*Precision Medicine/methods
Early Diagnosis

@article {pmid41314744,
year = {2025},
author = {Gunasekaran, B and Arifin, AH and Yu, WH and Hanafi, S and Rao, KDK and Salvamani, S},
title = {Precision medicine in neurodegenerative diseases: From research to clinical practice.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {1-52},
doi = {10.1016/bs.pbr.2025.08.006},
pmid = {41314744},
issn = {1875-7855},
mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/therapy/genetics/diagnosis ; Biomarkers ; },
abstract = {The chapter outlines how precision medicine is reshaping the way neurodegenerative diseases (NDs) which includes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are understood, diagnosed, and treated. It discusses the limitations of current therapies, which mainly address symptoms without altering disease progression. Genetic and molecular factors that influence disease development are described, including distinctions between familial and sporadic forms. The chapter also covers the roles of epigenetic changes, gene expression, protein dysfunction, mitochondrial DNA, and non-coding RNAs in NDs. Biomarkers in blood and cerebrospinal fluid, along with imaging techniques and digital tools, are presented as key elements in early diagnosis and disease monitoring. Patient stratification based on clinical features, molecular profiles, and biomarkers helps guide treatment decisions and improve outcomes. The chapter reviews ongoing developments in genotype-based drug design, gene therapy, pharmacogenomics, and personalized lifestyle strategies. Clinical case studies show how these approaches are being used in practice. The chapter also discusses challenges in applying precision medicine, such as trial design, data integration, unequal access, and regulatory hurdles. Finally, it highlights the future tools like single-cell transcriptomics, digital twins, and global research collaborations that aim to bring precision approaches into everyday care.},
}

Humans
*Precision Medicine/methods
*Neurodegenerative Diseases/therapy/genetics/diagnosis
Biomarkers

@article {pmid41314580,
year = {2025},
author = {Wang, X and Wang, D and Liu, J and Han, F and Liang, P and Yang, J and Xu, W and Ma, J and Wu, Y and An, X and Xue, Y and Chen, H and Zeng, L and Qu, Y and Ai, J},
title = {Systemic delivery of liposome-loaded microRNA-195 ameliorates spatial memory impairment in a rat model of chronic cerebral hypoperfusion.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149290},
doi = {10.1016/j.ijbiomac.2025.149290},
pmid = {41314580},
issn = {1879-0003},
abstract = {Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular dementia (VaD), including amyloid-β (Aβ) deposition, tau phosphorylation, microglial activation and neural circuit dysfunction. Developing multitarget therapeutics to effectively prevent the transition from MCI to AD and/or VaD remains an urgent challenge. Herein, we engineered a brain-targeted dual-modified PEGylated nanoliposome (LipTM@miR-195), incorporating mannose (MAN) and the trans-activating protein of HIV type 1 (TAT), which encapsulates polyethyleneimine (PEI) complesed microRNA-195 (miR-195). In a CCH rat model, tail-vein administration of LipTM@miR-195 (0.112 mg/kg) efficiently crossed the blood-brain barrier (BBB) without detectable side effects. Treatment reversed CCH-induced spatial learning and memory deficits, rescued neural circuit dysfunction, and suppressed elevated APP, BACE1, AT8 and CD68 levels. Collectively, these findings provide compelling evidence that LipTM@miR-195 nanoliposome holds therapeutic potential for CCH-induced cognitive impairment, thereby preventing the progression from MCI to AD and/or VaD.},
}

@article {pmid41314098,
year = {2025},
author = {Ye, M and Kim, JS and Shim, I},
title = {CB1 receptor activation and inhibition differentially modulate cognitive deficits and neuropathology in 3xTg-AD mice.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118818},
doi = {10.1016/j.biopha.2025.118818},
pmid = {41314098},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and progressive neuronal loss. The endocannabinoid system regulates synaptic function, inflammation, and redox homeostasis through cannabinoid receptor type 1 (CB1). This study aimed to determine whether pharmacological activation or inhibition of the CB1 receptor differentially modulates Alzheimer's disease-related pathology. 3xTg-AD mice received weekly intraperitoneal injections of the CB1 agonist ACEA (1 mg/kg) or the inverse agonist AM251 (1 mg/kg) from 6 to 12 months of age. Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze, while hippocampal tissues were analyzed for Aβ, p-Tau, glial markers (GFAP, Iba-1), cytokines (IL-1β, IL-10), oxidative stress markers (SOD, GSH, MDA), and neuronal viability (NeuN). Cerebral glucose metabolism was evaluated using [1] [8]F-FDG positron emission tomography (PET). ACEA administration reduced tau phosphorylation, glial activation, IL-1β expression, and oxidative stress, while increasing IL-10 levels, neuronal preservation, and cerebral glucose metabolism. AM251 treatment aggravated tau pathology, neuroinflammation, oxidative imbalance, and cognitive impairment. Double immunofluorescence demonstrated CB1 receptor colocalization with both Iba-1-positive microglia and GFAP-positive astrocytes, with CB1 predominantly localized to microglia, suggesting a microglia-dependent mechanism underlying CB1-mediated neuroprotection. Aβ levels were not affected by either treatment. Chronic CB1 receptor activation attenuates tau-associated pathology and metabolic dysfunction in 3xTg-AD mice, indicating the therapeutic relevance of CB1 signaling modulation in neurodegenerative disorders.},
}

@article {pmid41313999,
year = {2025},
author = {Pei, Z and Zhu, L and Ren, H and Liu, Y and Shi, X and Lin, Y and Wang, J and Li, P and Wang, P and Ji, Y and Zhou, Y and Tang, X and Jiang, X and Tong, X and Guo, Y},
title = {EEG-based stratification in Alzheimer's disease: Cognitive progression, pathological marker associations, and therapeutic interventions.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {182},
number = {},
pages = {2111440},
doi = {10.1016/j.clinph.2025.2111440},
pmid = {41313999},
issn = {1872-8952},
abstract = {OBJECTIVE: Clinical cognitive and pathological marker stratification systems have evolved separately, causing mismatches that limit their clinical use. This study retrospectively validated the link between EEG and clinical symptoms, pathological markers, and the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS).

METHODS: This multicenter study involved 308 Alzheimer's patients (AD), 176 with Parkinson's (PD), and 181 normal controls. Resting-state EEG were analyzed to identify four oscillation modes. An EEG-based cognitive risk system was created and validated, also evaluating its effect on rTMS therapy effectiveness.

RESULTS: EEG oscillation changes correlated with cognitive decline, revealing distinct brain network disruptions in AD and PD. These oscillation changes were associated with AD biomarkers, particularly tau hyperphosphorylation. Multicenter validation showed an 83% concordance with the Clinical Dementia Rating Scale, and EEG stratification enhanced rTMS therapeutic efficacy.

CONCLUSIONS: This study showed that EEG-based stratification can assess cognitive function, track disease progression, identify key intervention periods, and improve patient selection for better treatment outcomes in clinical settings.

SIGNIFICANCE: This study demonstrates that EEG can connect disease processes to clinical symptoms at a molecular level, offering a unified framework for improved dementia management. This method allows for dynamic monitoring and precise neuromodulation, enhancing personalized care for neurodegenerative diseases.},
}

@article {pmid41313889,
year = {2025},
author = {Jelčić, A and Talić, S and Odak, I and Mlakić, M and Lasić, Z and Roca, S and Šagud, I and Bruketa, T and Bosnar, M and Barić, D and Škorić, I},
title = {Exploring the selective butyrylcholinesterase inhibition potential of phenol carbamates: Experimental and computational study.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 3},
pages = {118375},
doi = {10.1016/j.ejmech.2025.118375},
pmid = {41313889},
issn = {1768-3254},
abstract = {A series of fourteen novel phenol carbamates was synthesized and evaluated as potential selective butyrylcholinesterase (BChE) inhibitors targeting cholinergic dysfunction in Alzheimer's disease (AD). The compounds were prepared efficiently from resveratrol analogs via a Wittig reaction followed by carbamoylation, and their structures were confirmed by NMR, MS, and HRMS analyses. All derivatives were screened for inhibitory activity against acetylcholinesterase (AChE) and BChE using a modified Ellman method. None of the compounds inhibited AChE, whereas all selectively inhibited BChE, with IC50 values ranging from 0.045 to 6.840 μM. The most potent inhibitor, compound 13, bearing a pyrrolidine moiety, exhibited an IC50 value of 0.045 μM, outperforming the reference drug galantamine by more than two orders of magnitude. Molecular docking and dynamics simulations confirmed strong π-π and alkyl-π interactions between the ligands and the enzyme's active site, accounting for their high affinity and selectivity. In silico ADME(T) analysis predicted excellent intestinal absorption, blood-brain barrier penetration, and low cytotoxicity, while minor genotoxicity alerts were observed for a few derivatives. In vitro cytotoxicity assays in HepG2 cells confirmed the absence of toxicity at concentrations up to 30 μM. These results highlight methoxy-substituted phenol carbamates, particularly compound 13, as promising lead structures for the design of selective BChE inhibitors and potential therapeutic agents for the treatment of AD.},
}

@article {pmid41313642,
year = {2025},
author = {Mangalmurti, A and Zengeler, KE and Hollis, A and Golden, E and Riddlemoser, G and Lukens, JR},
title = {Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70943},
doi = {10.1002/alz.70943},
pmid = {41313642},
issn = {1552-5279},
support = {ADSF-21-816651/ALZ/Alzheimer's Association/United States ; /NH/NIH HHS/United States ; R01AG071996/AG/NIA NIH HHS/United States ; R01AG087406/AG/NIA NIH HHS/United States ; RF1AG078684/AG/NIA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //The Steven A Newman AD Award/ ; //Rick Sharp Foundation/ ; //Harrison Family Foundation/ ; T32GM007267//Medical Scientist Training Program/ ; T32AI007496//Immunology Training Program/ ; T32AI007496//National Institute of Allergy and Infectious Diseases/ ; T32GM156694/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; *Plaque, Amyloid/pathology/metabolism ; Disease Models, Animal ; *Microglia/metabolism/pathology ; *Lectins, C-Type/metabolism/genetics ; Mice ; Mice, Transgenic ; Mice, Knockout ; Macrophages/metabolism ; Amyloid beta-Peptides/metabolism ; Humans ; Brain/pathology/metabolism ; },
abstract = {INTRODUCTION: CLEC7A is a surface receptor that is highly upregulated on microglia in many Alzheimer's disease (AD) models. Little is known about the role that microglial CLEC7A signaling plays in AD-related pathogenesis.

METHODS: We utilized an inducible, central nervous system (CNS) macrophage-specific knockout of Clec7a to evaluate the role of CLEC7A in the 5xFAD mouse model of AD at 5 months of age. We used immunofluorescence microscopy, single-nuclei RNA sequencing, along with biochemical assays, to evaluate plaque burden, microglial activity, and neuronal health.

RESULTS: CNS macrophage-targeted deletion of CLEC7A in 5xFAD mice led to a twofold increase in plaque burden, exacerbated neuritic dystrophy, and altered the expression of neuronal health genes, but did not appreciably impact microglial activation, plaque engulfment, or disease-associated microglia acquisition.

DISCUSSION: These findings identify protective roles for CLEC7A in AD-related amyloidosis and suggest that CLEC7A-targeting therapeutics may offer promising strategies for treatment of AD.

HIGHLIGHTS: Conditional loss of CLEC7A in central nervous system (CNS) macrophages of 5xFAD mice results in increased amyloid beta deposition. Loss of CLEC7A does not alter the disease-associated microglia transcriptional program or affect the recruitment of microglia to plaque surfaces. Exacerbation of amyloid deposition with loss of CNS-macrophage CLEC7A is associated with worsened neuronal health highlighted by increased neuritic dystrophy.},
}

Animals
*Alzheimer Disease/pathology/metabolism/genetics
*Plaque, Amyloid/pathology/metabolism
Disease Models, Animal
*Microglia/metabolism/pathology
*Lectins, C-Type/metabolism/genetics
Mice
Mice, Transgenic
Mice, Knockout
Macrophages/metabolism
Amyloid beta-Peptides/metabolism
Humans
Brain/pathology/metabolism

@article {pmid41312814,
year = {2025},
author = {Akpınar, O and Nazıroğlu, M},
title = {Glutathione and TRPM2 Inhibition Reduce Amyloid-Beta and Lipopolysaccharide-Induced Apoptosis, Inflammation, and Oxidative Stress in Microglial Cells.},
journal = {Cell biology international},
volume = {},
number = {},
pages = {},
doi = {10.1002/cbin.70109},
pmid = {41312814},
issn = {1095-8355},
support = {//This study was supported by the Scientific Research Projects Coordination Unit (BAP) of Süleyman Demirel University (project number: TDK-2021-8387). Project owner was Mustafa Nazıroğlu./ ; },
abstract = {Microglia cells impacted by inflammation and Alzheimer's disease produce toxic reactive oxygen species (ROS), emit signaling molecules, and death as a result of microglia being active due to excessive Ca[2+] entering the cells. The TRPM2 channel plays a crucial role in Ca[2+] permeability, inflammation, ROS, and apoptosis changes in the BV2 microglia cells, while glutathione (GSH) treatment reduces the changes through TRPM2 inhibition. However, the effect of TRPM2 inhibitors and GSH treatment on oxidative stress, inflammation, and apoptotic values in BV2 microglia cells activated with LPS and amyloid-beta (Aβ) has not been investigated yet. The study aimed to assess the effects of TRPM2 inhibition and GSH treatment on the values in BV2 cells activated with LPS and Aβ. BV2 cells were divided into five groups: control (CNT), LPS, Aβ, Aβ + LPS, and Aβ + LPS + GSH. Increased levels of inflammation biomarkers (TNF-α, IL-1β, and IL-6), intracellular Ca[2+] level, cytosolic ROS, mitochondrial membrane dysfunction, cell death, apoptosis, caspases (caspase-3, -8, and -9), and TRPM2 current density were observed in the cells stimulated with LPS and Aβ. These values increased more when LPS and Aβ were incubated together. However, these apoptotic, inflammatory, and oxidant levels decreased in cells treated with GSH and TRPM2 blockers. In conclusion, the involvement of TRPM2 stimulation was demonstrated on Aβ and LPS-induced Ca[2+] entry, oxidative stress, inflammation, and apoptosis parameters in microglia cells. TRPM2 inhibition by GSH treatment seems to be a potential source for the prevention of Aβ and LPS-induced oxidative stress, apoptosis, and inflammation.},
}

@article {pmid41312794,
year = {2025},
author = {Healy, M and Thomas, S and Brodtmann, A},
title = {Magnetic resonance imaging eligibility for anti-amyloid monoclonal antibody treatment for Alzheimer disease: a single-centre retrospective review for service planning.},
journal = {Internal medicine journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/imj.70254},
pmid = {41312794},
issn = {1445-5994},
}

@article {pmid41312566,
year = {2025},
author = {Kwinta, R and Morawiec, N and Bączyk, J and Kubicka-Bączyk, K and Adamczyk-Sowa, M},
title = {Aging immunity - the role of T and B cells in neurological disorders among older adults.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.106498},
pmid = {41312566},
issn = {0028-3843},
abstract = {INTRODUCTION: Immunosenescence is a natural process of immune system aging, which leads to significant changes in the functioning of both innate and adaptive immunity. Alterations in T and B lymphocytes can significantly impact the progression of neurological diseases including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

STATE OF THE ART: Immunosenescence affects T and B cell subsets, reducing their proliferative capacity and altering cytokine profiles. In MS, these changes promote disease progression and diminish responses to immunomodulatory therapies. In AD and PD, dysfunctional T and B cells contribute to sustained neuroinflammation, exacerbating neurodegeneration. ALS is similarly associated with altered adaptive immunity.

CLINICAL IMPLICATIONS: Recognizing how immunosenescent T and B cells contribute to disease in older adults is crucial for refining treatment strategies. These age-related immune changes may explain varied responses to therapies and highlight the need for novel approaches targeting the aged immune system in neurodegenerative diseases.

FUTURE DIRECTIONS: Future research should focus on identifying the mechanisms by which immunosenescent lymphocytes modulate neuroinflammation and neurodegeneration in aging populations. Novel biomarkers and immunomodulatory therapies tailored to older adults could significantly improve outcomes in patients with neurological diseases.},
}

@article {pmid41311387,
year = {2025},
author = {Zhou, Y and Wang, Y and Yang, H and Zhang, C and Meng, J and Zhang, L and Li, K and Huang, LL and Zhang, X and Luo, H and Zhang, Y},
title = {Sorafenib promotes the E3 ubiquitin ligase FBXW7 to increase tau degradation and ameliorate tauopathies.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {11},
pages = {5817-5831},
pmid = {41311387},
issn = {2211-3835},
abstract = {Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin-proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.},
}